Process for preparing quinazoline rho-kinase inhibitors and intermediates thereof

ABSTRACT

A process for the preparation of various quinazoline compounds which are useful as Rho-Kinase inhibitors, and thus having utility in the treatment of hypertension and other indications.

This application claims the benefit of the filing date of U.S.application Ser. No. 10/103,566 filed Mar. 22, 2002 and PCT ApplicationNo. PCT/US02/08659 filed Mar. 22, 2002.

FIELD OF THE INVENTION

The present invention relates to methods of producing quinazolinecompounds and derivatives thereof which are useful as Rho-kinaseInhibitors or intermediates thereof. Rho-kinase inhibitors are usefulfor inhibiting tumor growth, treating erectile dysfunction, and treatingother indications mediated by Rho-kinase, e.g., coronary heart disease.

BACKGROUND

The pathology of a number of human and animal diseases includinghypertension, erectile dysfunction, coronary cerebral circulatoryimpairments, neurodegenerative disorders and cancer can be linkeddirectly to changes in the actin cytoskeleton. These diseases pose aserious unmet medical need. The actin cytoskeleton is composed of ameshwork of actin filaments and actin-binding proteins found in alleukaryotic cells. In smooth muscle cells the assembly and disassembly ofthe actin cytoskeleton is the primary motor force responsible for smoothmuscle contraction and relaxation. In non-muscle cells, dynamicrearrangements of the actin cytoskeleton are responsible for regulatingcell morphology, cell motility, actin stress fiber formation, celladhesion and specialized cellular functions such as neurite retraction,phagocytosis or cytokinesis (Van Aelst, et al. Genes Dev 1997, 11,2295).

The actin cytoskeleton is controlled by a family of proteins that are asubset of the Ras superfamily of GTPases. This subset currently consistsof RhoA through E and RhoG (refereed to collectively as Rho), Rac 1 and2, Cdc42Hs and G25K and TC10 isoforms (Mackay, et al. J Biol Chem 1998,273, 20685). These proteins are GTP (guanine nucleotide triphosphate)binding proteins with intrinsic GTPase activity. They act as molecularswitches and cycles between inactive GDP (guanine nucleotidediphosphate) bound and active GTP bound states. Using biochemical andgenetic manipulations, it has been possible to assign functions to eachfamily member. Upon activation the Rho proteins controls the formationof actin stress fibers, thick bundles of actin filaments, and theclustering of integrins at focal adhesion complexes. When activated theRac proteins control the formation of lamellopodia or membrane ruffleson the cell surface and Cdc42 controls filopodia formation. Togetherthis family of proteins plays a critical part in the control of keycellular functions including cell movement, axonal guidance,cytokinesis, and changes in cell morphology, shape and polarity.

Depending on the cell type and the activating receptor, the Rho proteinscan control different biological responses. In smooth muscle cells, Rhoproteins are responsible for the calcium sensitization during smoothmuscle contraction. In non-smooth muscle cells the Rho GTPases areresponsible for the cellular responses to agonist such aslysophosphatidic acid (LPA), thrombin and thromboxane A₂ (Fukata, et al.Trends Pharcol Sci 2001, 22, 32). Agonist response is coupled throughheterotrimeric G proteins G_(alpha12) or G_(alpha13) (Goetzl, et al.Cancer Res 1999, 59, 4732; Buhl, et al. J Biol Chem 1995, 270, 24631)though other receptors may be involved. Upon activation Rho GTPasesactivate a number of downstream effectors including PIPS-kinase,Rhothekin, Rhophilin, PKN and Rho kinase isoforms ROCK-1/ROKbeta andROCK-1/ROKalpha (Mackay and Hall J Biol Chem 1998, 273, 20685;Aspenstrom Curr Opin Cell Biol 1999, 11, 95; Amano, et al. Exp Cell Res2000, 261, 44).

Rho kinase was identified as a RhoA interacting protein isolated frombovine brain (Matsui, et al. Embo J 1996, 15, 2208). It is a member ofthe myotonic dystrophy family of protein kinase and contains aserine/threonine kinase domain at the amino terminus, a coiled-coildomain in the central region and a Rho interaction domain at the carboxyterminus (Amano, et al. Exp Cell Res 2000, 261, 44). Its kinase activityis enhanced upon binding to GTP-bound RhoA and when introduced intocells, it can reproduce many of the activities of activated RhoA. Insmooth muscle cells Rho kinase mediates calcium sensitization and smoothmuscle contraction and inhibition of Rho kinase blocks 5-HT andphenylephrine agonist induced muscle contraction. When introduced intonon-smooth muscle cells, Rho kinase induces stress fiber formation andis required for the cellular transformation mediated by RhoA (Sahai, etal. Curr Biol 1999, 9, 136). Rho kinase regulates a number of downstreamproteins through phosphorylation, including myosin light chain (Somlyo,et al. J Physiol (Lond) 2000, 522 Pt 2, 177), the myosin light chainphosphatase binding subunit (Fukata, et al. J Cell Biol 1998, 141, 409)and LIM-kinase 2 (Sumi, et al. J Bio Chem 2001, 276, 670).

Inhibition of Rho kinase activity in animal models has demonstrated anumber of benefits of Rho kinase inhibitors for the treatment of humandiseases. Several patents have appeared claiming(+)-trans-4-(1-aminoethyl)-1-(pyridin-4-ylaminocarbonyl)cyclohexanedihydrochloride monohydrate (WO-00078351, WO-00057913) and substitutedisoquinolinesulfonyl (EP-00187371) compounds as Rho kinase inhibitorswith activity in animal models. These include models of cardiovasculardiseases such as hypertension (Uehata, et al. Nature 1997, 389, 990),atherosclerosis (Retzer, et al. FEBS Lett 2000, 466, 70), restenosis(Eto, et al. Am J Physiol Heart Circ Physiol 2000, 278, H1744; Negoro,et al. Biochem Biophys Res Commun 1999, 262, 211), cerebral ischemia(Uehata, et al. Nature 1997, 389, 990; Seasholtz, et al. Circ Res 1999,84, 1186; Hitomi, et al. Life Sci 2000, 67, 1929; Yamamoto, et al. JCardiovasc Pharmacol 2000, 35, 203), cerebral vasospasm (Sato, et al.Circ Res 2000, 87, 195; Kim, et al. Neurosurgery 2000, 46, 440), penileerectile dysfunction (Chitaley, et al. Nat Med 2001, 7, 119), centralnervous system disorders such as neuronal degeneration and spinal cordinjury (Hara, et al. J Neurosurg 2000, 93, 94; Toshima, et al. Stroke2000, 31, 2245) and in neoplasias where inhibition of Rho kinase hasbeen shown to inhibit tumor cell growth and metastasis (Itoh, et al. NatMed 1999, 5, 221; Somlyo, et al. Biochem Biophys Res Commun 2000, 269,652), angiogenesis (Uchida, et al. Biochem Biophys Res Commun 2000, 269,633; Gingras, et al. Biochem J 2000, 348 Pt 2, 273), arterial thromboticdisorders such as platelet aggregation (Klages, et al. J Cell Biol 1999,144, 745; Retzer, et al. Cell Signal 2000, 12, 645) and leukocyteaggregation (Kawaguchi, et al. Eur J Pharmacol 2000, 403, 203;Sanchez-Madrid, et al. Embo J 1999, 18, 501), asthma (Setoguchi, et al.Br J Pharmacol 2001, 132, 111; Nakahara, et al. Eur J Pharmacol 2000,389, 103), regulation of intraoccular pressure (Honjo, et al. InvestOpthalmol V is Sci 2001, 42, 137) and bone resorption (Chellaiah, et al.J Biol Chem 2000, 275, 11993; Zhang, et al. J Cell Sci 1995, 108, 2285).

The inhibition of Rho kinase activity in patients has benefits forcontrolling cerebral vasospasms and ischemia following subarachnoidhemorrhage (Pharma Japan 1995, 1470, 16).

SUMMARY OF THE INVENTION

The present invention provides methods of producing compounds useful asRho Kinase inhibitors and thus having utilities in the treatment ofhypertension, atherosclerosis, restenosis, cerebral ischemia, cerebralvasospasm, neuronal degeneration, spinal cord injury, cancers of thebreast, colon, prostate, ovaries, brain and lung and their metastases,thrombotic disorders, asthma, glaucoma and osteoporosis, as well aserectile dysfunction, i.e., erectile dysfunction mediated by Rho-kinase.Erectile dysfunction can be defined as an inability to obtain or sustainan erection adequate for intercourse, WO 94/28902, U.S. Pat. No.6,103,765 and U.S. Pat. No. 6,124,461.

The invention pertains to a process for the preparation of a compound ofFormula (I)

comprising reacting a compound of Formula 1

with a compound of Formula

to produce a compound of Formula 2

cyclizing 2 to form a compound of Formula 3

replacing the hydroxy group of 3 with a leaving group LGto form a compound of Formula 4

optionally isolating said compound of Formula 4;reacting a mixture of said compound of Formula 4 and a compound ofFormula 5

and optionallyisolating said compound of Formula (I);wherein in Formulae 3, 4, 5 and (I)a and c are each independently —CR₅═, —N═, or —NR₆—, wherein one of a orc is —NR₆—;

b is —CR₅= or —N═;

-   A is a 3-20 atom, cyclic or polycyclic moiety, e.g., containing 1-4    rings, which optionally contain 1-3 N, O or S atoms per ring, and    may optionally be aryl or heteroaryl, which cyclic or polycyclic    moiety may optionally be substituted up to 3 times by (i) C₁-C₁₀    alkyl or C₂-C₁₀-alkenyl, each optionally substituted with halogen up    to perhalo; (ii) C₃-C₁₀ cycloalkyl; (iii) aryl; (iv) heteroaryl; (v)    halogen; (vi) —CO—OR₈; (vii) —CO—R₈; (viii) cyano; (ix) —OR₈, (x)    —NR₈R₁₃; (xi) nitro; (xii) —CO—NR₈R₉; (xiii)    —C₁₋₁₀-alkyl-NR₈R₉; (xiv) —NR₈—CO—R₁₂; (xv) —NR₈—CO—OR₉; (xvi)    —NR₈—SO₂—R₉; (xvii) —SR₈; (xviii) —SO₂—R₈; (xix) —SO₂—NR₈R₉; or (xx)    NR₈—CO —NHR₉;-   R₁, R₆ and R₈-R₁₁ are each independently H or C₁₋₆ alkyl;-   R₂-R₅ are each independently (1) C₁₋₁₀ alkyl or C₂₋₁₀-alkenyl each    optionally substituted by amino, N-lower alkylamino, N,N-dilower    alkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR₁₀, —COR₁₄,    —OCOR₁₄, —OR₁₀, C₅₋₁₀-heteroaryl, C₅₋₁₀-heteroaryloxy, or    C₅₋₁₀-heteroaryl-C₁₋₁₀-alkoxy, halogen up to perhalo; (ii) C₃-C₁₀    cycloalkyl, in which 1-3 carbon atoms are optionally independently    replaced by O, N or S; (iii) C₃₋₁₀-cycloalkenyl; (iv) partially    unsaturated C₅₋₁₀-heterocyclyl; (v) aryl; (vi) heteroaryl; (vii)    halogen; (viii) —CO—OR₁₀; (ix) —OCOR₁₀; (x) —OCO₂R₁₀; (xi)    —CHO; (xii) cyano; (xiii) —OR₁₆; (xiv) —NR₁₀R₁₅; (xv) nitro; (xvi)    —CO—NR₁₀R₁₁; (xvii) —NR₁₀—CO—R₁₂; (xviii) —NR₁₀—CO—OR₁₁; (xix)    —NR₁₀—SO₂—R₁₂; (xx) —SR₁₆; (xxi) —SOR₁₆; (xxii) —SO₂—R₁₆; (xxiii)    —SO₂—NR₁₀R₁₁; (xxiv) NR₁₀—CO—NHR₁₁; (xxv) amidino; (xxvi)    guanidino; (xxvii) sulfo; (xxviii) —B(OH)₂; (xxix) —OCON(R₁₀)₂;    or (xxx) —NR₁₀CON(R₁₀)₂;-   R₁₂ is H, C₁₋₆-alkyl or C₅₋₁₀-aryl,-   R₁₃ is H, C₁₋₆-alkyl or C₁₋₆-alkoxy,-   R₁₄ is lower alkyl or phenyl;-   R₁₅ is lower alkyl, halogen, amino, N-lower alkyl amino, N,N-dilower    alkylamino, N-lower alkanoylamino, OH, CN, COOR₁₀, —COR₁₄ or —OCR₁₄;-   R₁₆ is hydrogen, C₁₋₆-alkyl optionally substituted by halogen, up to    perhalo, or C₅₋₁₀-heteroaryl;-   p=0, 1, 2 or 3;-   LG is Br or S-alkyl; and-   Q is CONH₂;    with the proviso that A is not phenyl.

Moreover, the invention pertains to a process for the preparation of acompound of Formula (I)

comprising reacting a compound of Formula 4

and a compound of Formula 5

wherein in Formulas 3, 4, 5 and (I)

-   a and c are each independently —CR₅═, —N═, or —NR₆—, wherein one of    a or c is —NR₆—;-   b is —CR₅═ or —N═;-   A is a 3-20 atom, cyclic or polycyclic moiety, e.g., containing 1-4    rings, which optionally contain 1-3 N, O or S atoms per ring, and    may optionally be aryl or heteroaryl, which cyclic or polycyclic    moiety may optionally be substituted up to 3 times by (i) C₁-C₁₀    alkyl or C₂-C₁₀-alkenyl, each optionally substituted with halogen up    to perhalo; (ii) C₃-C₁₀ cycloalkyl; (iii) aryl; (iv) heteroaryl; (v)    halogen; (vi) —CO—OR₈; (vii) —CO—R₈; (viii) cyano; (ix) —OR₈, (x)    —NR₈R₁₃; (xi) nitro; (xii) —CO—NR₈R₉; (xiii)    —C₁₋₁₀-alkyl-NR₈R₉; (xiv) —NR₈—CO—R₁₂; (xv) —NR₈—CO—OR₉; (xvi)    —NR₈—SO₂—R₉; (xvii) —SR₈; (xviii) —SO₂—R₈; (xix) —SO₂—NR₈R₉; or (xx)    NR₈—CO —NHR₉;-   R₁, R₆ and R₈-R₁₁ are each independently H or C₁₋₆ alkyl;-   R₂-R₅ are each independently (i) C₁₋₁₀ alkyl or C₂₋₁₀-alkenyl each    optionally substituted by amino, N-lower alkylamino, N,N-dilower    alkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR₁₀, —COR₁₄,    —OCOR₁₄, —OR₁₀, C₅₋₁₀-heteroaryl, C₅₋₁₀-heteroaryloxy, or    C₅₋₁₀-heteroaryl-C₁₋₁₀-alkoxy, halogen up to perhalo; (ii) C₃-C₁₀    cycloalkyl, in which 1-3 carbon atoms are optionally independently    replaced by O, N or S; (iii) C₃₋₁₀-cycloalkenyl; (iv) partially    unsaturated C₅₋₁₀-heterocyclyl; (v) aryl; (vi) heteroaryl; (vii)    halogen; (viii) —CO—OR₁₀; (ix) —OCOR₁₀; (x) —OCO₂R₁₀; (xi)    —CHO; (xii) cyano; (xiii) —OR₁₆; (xiv) —NR₁₀R₁₅; (xv) nitro; (xvi)    —CO—NR₁₀R₁₁; (xvii) —NR₁₀—CO—R₁₂; (xviii) —NR₁₀—CO—OR₁₁; (xix)    —NR₁₀—SO₂—R₁₂; (xx) —SR₁₆; (xxi) —SOR₁₆; (xxii) —SO₂—R₁₆; (xxiii)    —SO₂—NR₁₀R₁₁; (xxiv) NR₁₀—CO—NHR₁₁; (xxv) amidino; (xxvi)    guanidino; (xxvii) sulfo; (xxviii) —B(OH)₂; (xxix) —OCON(R₁₀)₂;    or (xxx) —NR₁₀CON(R₁₀)₂;-   R₁₂ is H, C₁₋₆-alkyl or C₅₋₁₀-aryl,-   R₁₃ is H, C₁₋₆-alkyl or C₁₋₆-alkoxy,-   R₁₄ is lower alkyl or phenyl;-   R₁₅ is lower alkyl, halogen, amino, N-lower alkyl amino, N,N-dilower    alkylamino, N-lower alkanoylamino, OH, CN, COOR₁₀, —COR₁₄ or    —OCOR₁₄;-   R₁₆ is hydrogen, C₁₋₆-alkyl optionally substituted by halogen, up to    perhalo, or C₅₋₁₀-heteroaryl;-   p=0, 1, 2 or 3; and-   LG is Br or S-alkyl;    with the proviso that A is not phenyl.

The invention also pertains to a process for the preparation of acompound of Formula 3

from a compound of Formula 2

comprising

-   mixing said compound of Formula 2, where Q is —CO—NH₂, with about    0.1 N to about 10 N aqueous hydroxide, and    -   heating from a temperature of about 30° C. to about 120° C.;        wherein-   A is a 3-20 atom, cyclic or polycyclic moiety, e.g., containing 1-4    rings, which optionally contain 1-3 N, O or S atoms per ring, and    may optionally be aryl or heteroaryl, which cyclic or polycyclic    moiety may optionally be substituted up to 3 times by (i) C₁-C₁₀    alkyl or C₂-C₁₀-alkenyl, each optionally substituted with halogen up    to perhalo; (ii) C₃-C₁₀ cycloalkyl; (iii) aryl; (iv) heteroaryl; (v)    halogen; (vi) —CO—OR₈; (vii) —CO—R₈; (viii) cyano; (ix) —OR₈, (x)    —NR₈R₁₃; (xi) nitro; (xii) —CO—NR₈R₉; (xiii)    —C₁₋₁₀-alkyl-NR₈R₉; (xiv) —NR₈—CO—R₁₂; (xv) —NR₈—CO—OR₉; (xvi)    —NR₈—SO₂—R₉; (xvii) —SR₈; (xviii) —SO₂—R₈; (xix) —SO₂—NR₈R₉; or (xx)    NR₈—CO —NHR₉;-   R₅ is (i) C₁₋₁₀ alkyl or C₂₋₁₀-alkenyl each optionally substituted    by amino, N-lower alkylamino, N,N-dilower alkylamino, N-lower    alkanoylamino, hydroxy, cyano, —COOR₁₀, —COR₁₄, —OCOR₁₄, —OR₁₀,    C₅₋₁₀-heteroaryl, C₅₋₁₀-heteroaryloxy, or    C₅₋₁₀-heteroaryl-C₁₋₁₀-alkoxy, halogen up to perhalo; (ii) C₃-C₁₀    cycloalkyl, in which 1-3 carbon atoms are optionally independently    replaced by O, N or S; (iii) C₃₋₁₀-cycloalkenyl; (iv) partially    unsaturated C₅₋₁₀-heterocyclyl; (v) aryl; (vi) heteroaryl; (vii)    halogen; (viii) —CO—OR₁₀; (ix) —OCOR₁₀; (x) —OCO₂R₁₀; (xi)    —CHO; (xii) cyano; (xiii) —OR₁₆; (xiv) —NR₁₀R₁₅; (xv) nitro; (xvi)    —CO—NR₁₀R₁₁; (xvii) —NR₁₀—CO—R₁₂; (xviii) —NR₁₀—CO—OR₁₁; (xix)    —NR₁₀—SO₂—R₁₂; (xx) —SR₁₆; (xxi) —SOR₁₆; (xxii) —SO₂—R₁₆; (xxiii)    —SO₂—NR₁₀R₁₁; (xxiv) NR₁₀—CO—NHR₁₁; (xxv) amidino; (xxvi)    guanidino; (xxvii) sulfo; (xxviii) —B(OH)₂; (xxix) —OCON(R₁₀)₂;    or (xxx) —NR₁₀CON(R₁₀)₂;-   p=0, 1, 2, or 3-   R₈-R₁₁ are each independently H or C₁₋₆ alkyl-   R₁₂ is H, C₁₋₆-alkyl or C₅₋₁₀-aryl,-   R₁₃ is H, C₁₋₆-alkyl or C₁₋₆-alkoxy,-   R₁₄ is lower alkyl or phenyl;-   R₁₅ is lower alkyl, halogen, amino, N-lower alkyl amino, N,N-dilower    alkylamino, N-lower alkanoylamino, OH, CN, COOR₁₀, —COR₁₄ or    —OCOR₁₄;-   R₁₆ is hydrogen, C₁₋₆-alkyl optionally substituted by halogen, up to    perhalo, or C₅₋₁₀-heteroaryl,    and wherein Formulas 2 and 3 encompass tautomers, optical isomers,    or salts thereof.

The invention also pertains to a process for the preparation of acompound of Formula 3,

from a carboxylic acid of Formula A-CO₂H and a compound of Formula 1,

comprising, in a single vessel,

-   treating said carboxylic acid with a chlorinating agent, with    optional addition of a catalytic amount of DMF, to form an acid    chloride of Formula A-CO—Cl;-   adding a non-nucleophilic amine base and a non-protic solvent with    stirring at room temperature to form a compound of Formula 2;

andadding of a base and heating the mixture up to about 50° C.; for asufficient time to effect reaction;wherein Q is CO—NH₂,

-   A is a 3-20 atom, cyclic or polycyclic moiety, e.g., containing 1-4    rings, which optionally contain 1-3 N, O or S atoms per ring, and    may optionally be aryl or heteroaryl, which cyclic or polycyclic    moiety may optionally be substituted up to 3 times by (i) C₁-C₁₀    alkyl or C₂-C₁₀-alkenyl, each optionally substituted with halogen up    to perhalo; (ii) C₃-C₁₀ cycloalkyl; (iii) aryl; (iv) heteroaryl; (v)    halogen; (vi) —CO—OR₈; (vii) —CO—R₈; (viii) cyano; (ix) —OR₈, (x)    —NR₈R₁₃; (xi) nitro; (xii) —CO—NR₈R₉; (xiii)    —C₁₋₁₀-alkyl-NR₈R₉; (xiv) —NR₈—CO—R₁₂; (xv) —NR₈—CO—OR₉; (xvi)    —NR₈—SO₂—R₉; (xvii) —SR₈; (xviii) —SO₂—R₈; (xix) —SO₂—NR₈R₉; or (xx)    NR₈—CO —NHR₉;-   R₅ is (i) C₁-C₁₀ alkyl or C₂₋₁₀-alkenyl each optionally substituted    by amino, N-lower alkylamino, N,N-dilower alkylamino, N-lower    alkanoylamino, hydroxy, cyano, —COOR₁₀, —COR₁₄, —OCOR₁₄, —OR₁₀,    C₅₋₁₀-heteroaryl, C₅₋₁₀-heteroaryloxy, or    C₅₋₁₀-heteroaryl-C₁₋₄₀-alkoxy, halogen up to perhalo; (ii) C₃-C₁₀    cycloalkyl, in which 1-3 carbon atoms are optionally independently    replaced by O, N or S; (iii) C₃₋₄₀-cycloalkenyl; (iv) partially    unsaturated C₅₋₁₀-heterocyclyl; (v) aryl; (vi) heteroaryl; (vii)    halogen; (viii) —CO—OR₁₀; (ix) —OCOR₁₀; (x) —OCO₂R₁₀; (xi)    —CHO; (xii) cyano; (xiii) —OR₁₆; (xiv) —NR₁₀R₁₅; (xv) nitro; (xvi)    —CO—NR₁₀R₁₁; (xvii) —NR₁₀—CO—R₁₂; (xviii) —NR₁₀—CO—OR₁₁; (xix)    —NR₁₀—SO₂—R₁₂; (xx) —SR₁₆; (xxi) —SOR₁₆; (xxii) —SO₂—R₁₆; (xxiii)    —SO₂—NR₁₀R₁₁; (xxiv) NR₁₀—CO—NHR₁₁; (xxv) amidino; (xxvi)    guanidino; (xxvii) sulfo; (xxviii) —B(OH)₂; (xxix) —OCON(R₁₀)₂;    or (xxx) —NR₁₀CON(R₁₀)₂;-   p=0, 1, 2, or 3-   R₈-R₁₁ are each independently H or C₁₋₆ alkyl R₁₂ is H, C₁₋₆-alkyl    or C₅₋₁₀-aryl,-   R₁₃ is H, C₁₋₆-alkyl or C₁₋₆-alkoxy,-   R₁₄ is lower alkyl or phenyl;-   R₁₅ is lower alkyl, halogen, amino, N-lower alkyl amino, N,N-dilower    alkylamino, N-lower alkanoylamino, OH, CN, COOR₁₀, —COR₁₄ or    —OCOR₁₄;-   R₁₆ is hydrogen, C₁₋₆-alkyl optionally substituted by halogen, up to    perhalo, or C₅₋₁₀-heteroaryl,    and wherein Formulas 2 and 3 encompass tautomers, optical isomers,    or salts thereof.

The invention also pertains to a process for the preparation of acompound of Formula (I)

comprising replacing the hydroxy group of a compound of Formula 3

with a leaving group LGto form a compound of Formula 4

optionally isolating said compound of Formula 4; reacting a mixture ofsaid compound of Formula 4 and a compound of Formula 5

and optionallyisolating said compound of Formula (I);wherein in Formulae 3, 4, 5 and (I)a and c are each independently —CR₅═, —N═, or —NR₆—, wherein one of a orc is —NR₆—;

b is —CR₅═ or —N═;

-   A is a 3-20 atom, cyclic or polycyclic moiety, e.g., containing 1-4    rings, which optionally contain 1-3 N, O or S atoms per ring, and    may optionally be aryl or heteroaryl, which cyclic or polycyclic    moiety may optionally be substituted up to 3 times by (i) C₁-C₁₀    alkyl or C₂-C₁₀-alkenyl, each optionally substituted with halogen up    to perhalo; (ii) C₃-C₁₀ cycloalkyl; (iii) aryl; (iv) heteroaryl; (v)    halogen; (vi) —CO—OR₈; (vii) —CO—R₈; (viii) cyano; (ix) —OR₈, (x)    —NR₈R₁₃; (xi) nitro; (xii) —CO—NR₈R₉; (xiii)    —C₁₋₁₀-alkyl-NR₈R₉; (xiv) —NR₈—CO—R₁₂; (xv) —NR₈—CO—OR₉; (xvi)    —NR₈—SO₂—R₉; (xvii) —SR₈; (xviii) —SO₂—R₈; (xix) —SO₂—NR₈R₉; or (xx)    NR₈—CO —NHR₉;-   R₁, R₆ and R₈-R₁₁ are each independently H or C₁₋₆ alkyl;-   R₂-R₅ are each independently (i) C₁₋₁₀ alkyl or C₂₋₁₀-alkenyl each    optionally substituted by amino, N-lower alkylamino, N,N-dilower    alkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR₁₀, —COR₁₄,    —OCOR₁₄, —OR₁₀, C₅₋₁₀-heteroaryl, C₅₋₁₀-heteroaryloxy, or    C₅₋₁₀-heteroaryl-C₁₋₁₀-alkoxy, halogen up to perhalo; (ii) C₃-C₁₀    cycloalkyl, in which 1-3 carbon atoms are optionally independently    replaced by O, N or S; (iii) C₃₋₁₀-cycloalkenyl; (iv) partially    unsaturated C₅₋₁₀-heterocyclyl; (v) aryl; (vi) heteroaryl; (vii)    halogen; (viii) —CO—OR₁₀; (ix) —OCOR₁₀; (x) —OCO₂R₁₀; (xi)    —CHO; (xii) cyano; (xiii) —OR₁₆; (xiv) —NR₁₀R₁₅; (xv) nitro; (xvi)    —CO—NR₁₀R₁₁; (xvii) —NR₁₀—CO—R₁₂; (xviii) —NR₁₀—CO—OR₁₁; (xix)    —NR₁₀—SO₂—R₁₂; (xx) —SR₁₆; (xxi) —SOR₁₆; (xxii) —SO₂—R₁₆; (xxiii)    —SO₂—NR₁₀R₁₁; (xxiv) NR₁₀—CO—NHR₁₁; (xxv) amidino; (xxvi)    guanidino; (xxvii) sulfo; (xxviii) —B(OH)₂; (xxix) —OCON(R₁₀)₂;    or (xxx) —NR₁₀CON(R₁₀)₂;-   R₁₂ is H, C₁₋₆-alkyl or C₅₋₁₀-aryl,-   R₁₃ is H, C₁₋₆-alkyl or C₁₋₆-alkoxy,-   R₁₄ is lower alkyl or phenyl;-   R₁₅ is lower alkyl, halogen, amino, N-lower alkyl amino, N,N-dilower    alkylamino, N-lower alkanoylamino, OH, CN, COOR₁₀, —COR₁₄ or    —OCOR₁₄;-   R₁₆ is hydrogen, C₁₋₆-alkyl optionally substituted by halogen, up to    perhalo, or C₅₋₁₀-heteroaryl;-   p=0, 1, 2 or 3; and-   LG is Br or S-alkyl    with the proviso that A is not phenyl.

The invention also pertains to a process for the preparation of acompound of Formula (I)

comprising reacting a compound of Formula 1

with a compound of Formula

to produce a compound of Formula 2

cyclizing 2 to form a compound of Formula 3

replacing the hydroxy group of 3 with a leaving groupto form a compound of Formula 4′

optionally isolating said compound of Formula 4′;reacting a mixture of said compound of Formula 4′ and a compound ofFormula 5

wherein in Formulas 3, 4′, 5 and (I)a and c are each independently —CR₅═, —N═, or —NR₆—, wherein one of a orc is —NR₆—;

b is —CR₅═ or —N═;

-   A is a 3-20 atom, cyclic or polycyclic moiety, e.g., containing 1-4    rings, which optionally contain 1-3 N, O or S atoms per ring, and    may optionally be aryl or heteroaryl, which cyclic or polycyclic    moiety may optionally be substituted up to 3 times by (i) C₁-C₁₀    alkyl or C₂-C₁₀-alkenyl, each optionally substituted with halogen up    to perhalo; (ii) C₃-C₁₀ cycloalkyl; (iii) aryl; (iv) heteroaryl; (v)    halogen; (vi) —CO—OR₈; (vii) —CO—R₈; (viii) cyano; (ix) —OR₈, (x)    —NR₈R₁₃; (xi) nitro; (xii) —CO—NR₈R₉; (xiii)    —C₁₋₁₀-alkyl-NR₈R₉; (xiv) —NR₈—CO—R₁₂; (xv) —NR₈—CO—OR₉; (xvi)    —NR₈—SO₂—R₉; (xvii) —SR₈; (xviii) —SO₂—R₈; (xix) —SO₂—NR₈R₉; or (xx)    NR₈—CO—NHR₉;-   R₁, R₆ and R₈-R₁₁ are each independently H or C₁₋₆ alkyl;-   R₂-R₅ are each independently (i) C₁₋₁₀ alkyl or C₂₋₁₀-alkenyl each    optionally substituted by amino, N-lower alkylamino, N,N-dilower    alkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR₁₀, —COR₁₄,    —OCOR₁₄, —OR₁₀, C₅₋₁₀-heteroaryl, C₅₋₁₀-heteroaryloxy, or    C₅₋₁₀-heteroaryl-C₁₋₁₀-alkoxy, halogen up to perhalo; (ii) C₃-C₁₀    cycloalkyl, in which 1-3 carbon atoms are optionally independently    replaced by O, N or S; (iii) C₃₋₁₀-cycloalkenyl; (iv) partially    unsaturated C₅₋₁₀-heterocyclyl; (v) aryl; (vi) heteroaryl; (vii)    halogen; (viii) —CO—OR₁₀; (ix) —OCOR₁₀; (x) —OCO₂R₁₀; (xi)    —CHO; (xii) cyano; (xiii) —OR₁₆; (xiv) —NR₁₀R₁₅; (xv) nitro; (xvi)    —CO—NR₁₀R₁₁; (xvii) —NR₁₀—CO—R₁₂; (xviii) —NR₁₀—CO—OR₁₁; (xix)    —NR₁₀—SO₂—R₁₂; (xx) —SR₁₆; (xxi) —SOR₁₆; (xxii) —SO₂—R₁₆; (xxiii)    —SO₂—NR₁₀R₁₁; (xxiv) NR₁₀—CO—NHR₁₁; (xxv) amidino; (xxvi)    guanidino; (xxvii) sulfo; (xxviii) —B(OH)₂; (xxix) —OCON(R₁₀)₂;    or (xxx) —NR₁₀CON(R₁₀)₂;-   R₁₂ is H, C₁₋₆-alkyl or C₅₋₁₀-aryl,-   R₁₃ is H, C₁₋₆-alkyl or C₁₋₆-alkoxy,-   R₁₄ is lower alkyl or phenyl;-   R₁₅ is lower alkyl, halogen, amino, N-lower alkyl amino, N,N-dilower    alkylamino, N-lower alkanoylamino, OH, CN, COOR₁₀, —COR₁₄ or    —OCOR₁₄;-   R₁₆ is hydrogen, C₁₋₆-alkyl optionally substituted by halogen, up to    perhalo, or C₅₋₁₀-heteroaryl; and-   p=0, 1, 2 or 3;-   LG is Cl, and-   Q is CN,    with the proviso that compound I is not

The invention also pertains to a process for the preparation of acompound of Formula (I)

comprising reacting a compound of Formula 4′

and a compound of Formula 5

wherein in Formulas 3, 4′, 5 and (I)

-   a and c are each independently —CR₅═, —N═, or —NR₆—, wherein one of    a or c is —NR₆—;-   b is —CR₅═ or —N═;-   A is a 3-20 atom, cyclic or polycyclic moiety, e.g., containing 1-4    rings, which optionally contain 1-3 N, O or S atoms per ring, and    may optionally be aryl or heteroaryl, which cyclic or polycyclic    moiety may optionally be substituted up to 3 times by (i) C₁-C₁₀    alkyl or C₂-C₁₀-alkenyl, each optionally substituted with halogen up    to perhalo; (ii) C₃-C₁₀ cycloalkyl; (iii) aryl; (iv) heteroaryl; (v)    halogen; (vi) —CO—OR₈; (vii) —CO—R₈; (viii) cyano; (ix) —OR₈, (x)    —NR₈R₁₃; (xi) nitro; (xii) —CO—NR₈R₉; (xiii)    —C₁₋₁₀-alkyl-NR₈R₉; (xiv) —NR₈—CO—R₁₂; (xv) —NR₈—CO—OR₉; (xvi)    —NR₈—SO₂—R₉; (xvii) —SR₈; (xviii) —SO₂—R₈; (xix) —SO₂—NR₈R₉; or (xx)    NR₈—CO—NHR₉;-   R₁, R₆ and R₈-R₁₁ are each independently H or C₁₋₆ alkyl;-   R₂-R₅ are each independently (i) C₁₋₁₀ alkyl or C₂₋₁₀-alkenyl each    optionally substituted by amino, N-lower alkylamino, N,N-dilower    alkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR₁₀, —COR₁₄,    —OCOR₁₄, —OR₁₀, C₅₋₁₀-heteroaryl, C₅₋₁₀-heteroaryloxy, or    C₅₋₁₀-heteroaryl-C₁₋₁₀-alkoxy, halogen up to perhalo; (ii) C₃-C₁₀    cycloalkyl, in which 1-3 carbon atoms are optionally independently    replaced by O, N or S; (iii) C₃₋₁₀-cycloalkenyl; (iv) partially    unsaturated C₅₋₁₀-heterocyclyl; (v) aryl; (vi) heteroaryl; (vii)    halogen; (viii) —CO—OR₁₀; (ix) —OCOR₁₀; (x) —OCO₂R₁₀; (xi)    —CHO; (xii) cyano; (xiii) —OR₁₆; (xiv) —NR₁₀R₁₅; (xv) nitro; (xvi)    —CO—NR₁₀R₁₁; (xvii) —NR₁₀—CO—R₁₂; (xviii) —NR₁₀—CO—OR₁₁; (xix)    —NR₁₀—SO₂—R₁₂; (xx) —SR₁₆; (xxi) —SOR₁₆; (xxii) —SO₂—R₁₆; (xxiii)    —SO₂—NR₁₀R₁₁; (xxiv) NR₁₀—CO—NHR₁₁; (xxv) amidino; (xxvi)    guanidino; (xxvii) sulfo; (xxviii) —B(OH)₂; (xxix) —OCON(R₁₀)₂;    or (xxx) —NR₁₀CON(R₁₀)₂;-   R₁₂ is H, C₁₋₆-alkyl or C₅₋₁₀-aryl,-   R₁₃ is H, C₁₋₆-alkyl or C₁₋₆-alkoxy,-   R₁₄ is lower alkyl or phenyl;-   R₁₅ is lower alkyl, halogen, amino, N-lower alkyl amino, N,N-dilower    alkylamino, N-lower alkanoylamino, OH, CN, COOR₁₀, —COR₁₄ or    —OCOR₁₄;-   R₁₆ is hydrogen, C₁₋₆-alkyl optionally substituted by halogen, up to    perhalo, or C₅₋₁₀-heteroaryl; and-   p=0, 1, 2 or 3;    with the proviso that compound I is not

The invention also pertains to a process for the preparation of acompound of Formula I′

wherein Y is ═N— or ═CR₁₇,

-   X is (CH₂)_(x)—, —O—(CH₂)_(n)—, —S—(CH₂)_(n)—, —NR₇—CO—(CH₂)_(n)—,-   —NR₇—SO₂—(CH₂)_(n)—, —NR₇—(CH₂)_(n)—, or —(O)C—NR₇—,    each n is an integer which is independently 0, 1, 2 or 3,    x is 0-3    p is 0-3    a and c are each independently —CR5═, —N═, or —NR6-, wherein one of    a or c is —NR₆—, and b is —CR5═ or —N═;    A is H, halogen, —CO—OR₈, —CO—R₈, cyano, —OR₈, —NR₈R₉, —CO—NR₈R₉,    —NR₈—CO—R₉, —NR₈—CO—OR₉, —NR₈—SO₂—R₉, —SR₈, —SO₂—R₈, —SO₂—NR₈R₉,    NR₈—CO—NHR₉, or    A is a 3-20 atom, cyclic or polycyclic moiety, containing 1-4 rings,    which optionally contain 1-3 N, O or S atoms per ring, and may    optionally be aryl or heteroaryl, which cyclic or polycyclic moiety    may optionally be substituted up to 3 times by (i) C₁-C₁₀ alkyl or    C₂-C₁₀— alkenyl, each optionally substituted with halogen up to    perhalo; (ii) C₃-C₁₀ cycloalkyl; (iii) aryl; (iv) heteroaryl; (v)    halogen; (vi) —CO—OR₈; (vii) —CO—R₈; (viii) cyano; (ix) —OR₈; (x)(x)    —NR₈R₁₃; (xi) nitro; (xii) —CO—NR₈R₉; (xiii)    —C₁₋₁₀-alkyl-NR₈R₉; (xiv) —NR₈—CO—R₁₂; (xv) —NR₈CO—OR₉; (xvi)    —NR₈—SO₂—R₉; (xvii) —SR₈; (xviii) —SO₂—R₈; (xix) —SO₂—NR₈R₉; or (xx)    NR₈—CO—NHR₉;    Ring B is optionally independently substituted up to 3 times in any    position by R₅,    R₁ and R₆₋₁₁ are each independently hydrogen or C₁₋₆alkyl,    R₂-R₅ are each independently (i) hydrogen, (ii) C₁₋₁₀ alkyl or    C₂₋₁₀-alkenyl each optionally substituted by amino, N-lower    alkylamino, N,N-dilower alkylamino, N-lower alkanoylamino, hydroxy,    cyano, —COOR₁₀, —COR₁₄, —OCOR₁₄, —OR₁₀, C₅₋₁₀-heteroaryl,    C₅₋₁₀-heteroaryloxy, or C₅₋₁₀-heteroaryl-C₁₋₁₀-alkoxy, halogen up to    perhalo; (iii) C₃₋₁₀ cycloalkyl, in which 1-3 carbon atoms are    optionally independently replaced by O, N or S; (iv)    C₃₋₄₀-cycloalkenyl; (v) partially unsaturated    C₅₋₁₀-heterocyclyl; (vi) aryl; (vii) heteroaryl; (viii)    halogen; (ix) —CO—OR₁₀; (x) —OCOR₁₀; (xi) —OCO₂R₁₀; (xii)    —CHO; (xiii) cyano; (xiv) —OR₁₆; (xv) —NR₁₀R₁₅; (xvi) nitro; (xvii)    —CO—NR₁₀R₁₁; (xviii) —NR₁₀—CO—R₁₂; (xix) —NR₁₀—CO—OR₁₁; (xx)    —NR₁₀—SO₂R₁₂; (xxi) —SR₁₆; (xxii) —SOR₁₆; (xxiii) —SO₂—R₁₆; (xxiv)    —SO₂—NR₁₀R₁₁; (xxv) NR₁₀—CO—NHR₁₁; (xxvi) amidino; (xxvii)    guanidine; (xxviii) sulfo; (xxix) —B(OH)₂; (xxx) —OCON(R₁₀)₂;    or (xxxi) —NR₁₀CON(R₁₀)₂;    R₁₂ is H, C₁₋₆-alkyl or C₅₋₁₀-aryl,    R₁₃ is H, C₁₋₆-alkyl or C₁₋₆-alkoxy,    R₁₄ is C₁₋₆ alkyl or phenyl;    R₁₅ is C₁₋₆ alkyl, halogen, amino, N-lower alkyl amino, N,N dilower    alkylamino, N-lower alkanoylamino, OH, CN, COOR₁₀, —COR₁₄ or    —OCOR₁₄;    R₁₆ is hydrogen, C₁₋₆-alkyl optionally substituted by halogen, up to    perhalo, or C₅₋₁₀-heteroaryl; and    R₁₇ is H, C₁₋₆ alkyl or CN,    or a pharmaceutically acceptable salt thereof,    with the provisos that A is not hydrogen when x is 0, and that    Formula I is not

said process comprising(a) reacting a compound of Formula II

with a compound of Formula III

in the presence of a base, to produce a compound of Formula IV

and optionally further reacting IV with arylboronic acid or A-NH₂, or(b) reacting a substituted benzoyl chloride with dimethylamine toproduce a compound of Formula V

wherein R′″ is (i) C₁-C₁₀ alkyl or C₂-C₁₀-alkenyl, each optionallysubstituted with halogen up to perhalo; (ii) C₃-C₁₀ cycloalkyl; (iii)aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR₈; (vii) —CO—R₈; (viii)cyano; (ix) —OR₈, (x) (x) —NR₈R₁₃; (xi) nitro; (xii) —CO—NR₈R₉; (xiii)—C₁₋₁₀-alkyl-NR₈R₉; (xiv) —NR₈—CO—R₁₂; (xv) —NR₈—CO—OR₉; (xvi)—NR₈—SO₂—R₉; (xvii) —SR₈; (xviii) —SO₂—R₈; (xix) —SO₂—NR₈R₉; or (xx)NR₈—CO—NHR₉, reacting V with chloro-2-amino-benzonitrile to produce acompound of Formula VI

and reacting VI with aminoindazole.

The invention also pertains to a process for preparing

comprising reacting 3-fluoro-4-phenylbenzoic acid

with 4-bromo-2-fluorobiphenyl to produce2[(3-fluoro-4-phenylphenyl)carbonylamino]-benzamide

cyclizing to produce 2-(3-fluoro-1,1′-biphenyl-4-yl)-4(3H)-quinazolinone

reacting to produce 4-chloro-2-(3-fluoro-4-phenylphenyl)quinazoline

and then reacting with aminoindazole to produce

In particular, the invention also pertains to a method of preparation ofa compound of Formula (I)

from the above described compounds of Formula 3 comprising the steps of

-   (1) heating of said Formula 3 compound with a chlorinating agent,    (with the optional addition of DMF), to form a compound of Formula    4′

-   (2) isolation of said compound of Formula 4′;-   (3) addition of a non-nucleophilic base to a mixture of said    compound of Formula 4′ and a compound of Formula 5

-   -   in a higher boiling solvent;

-   (4) heating said mixture at reflux (up from 5 to about 20 hours) for    a time sufficient to effect reaction; and

-   (5) isolation of said compound of Formula (I).

Moreover, the present invention pertains to a method of preparation of acompound of Formula 3

from a compound of Formula 2

comprising the steps of

-   (1) (a) mixing said compound of Formula 2, where Q is —CO—NH₂, with    about 0.1 N to about 10 N (or 20%) aqueous hydroxide, or-   (1) (b) mixing said compound of Formula 2, where Q is —CN,—with    about 0.1 N to about 10 N (or 20%) aqueous hydroxide and about 3- to    about 30% H₂O₂, or with about 0.5 to 2.5 M mineral acid,-   (2) heating the mixture from a temperature of about 30° C. to about    120° C.

The invention also pertains to a method of preparation of a compound ofFormula 3, from a carboxylic acid of Formula A-CO₂H and a compound ofFormula 1,

comprising the steps of

-   (1) treatment of the said carboxylic acid with a chlorinating agent,    with the optional addition of a catalytic amount of DMF, to form an    acid chloride of Formula A-CO—Cl;-   (2) addition of a non-nucleophilic amine base and a non-protic    solvent with stifling at room temperature to form the compound of    Formula 2; and-   (3) addition of a base and heating the mixture up to about 50° C.    (for about 90 minutes); for a sufficient time to effect reaction;    wherein the steps are conducted in a single vessel; and in Formulas    1, 2 and 3

Q is CO—NH₂;

and R₅, A, and p are as defined above; and the tautomers, opticalisomers and salts thereof.

A schematic representation of the methods of preparation encompassed bythis invention is summarized in Reaction Scheme 1 below. In thestructures depicted, A, R₁-R₅, a, b, c and p have the meanings describedabove.

In this embodiment, a mixture of nitrile or amide 1 and an aliphatic oraromatic acid chloride (A-CO—Cl, commercially available, preparedbeforehand from the carboxylic acid A-CO₂H, or prepared from thecarboxylic acid in situ) are coupled, in the presence of a base such asa dialkylamine, DMAP, pyridine and the like. The nitriles and amides arereadily available commercially, or if necessary, prepared from thecorresponding anthranilic acid or anthranilic acid ester bystraightforward means. The acid chlorides, A-CO—Cl starting materials,where not readily available commercially may be by standard preparatorymethods from the corresponding carboxylic acids(using chlorinatingreagents such as SOCl₂, phosgene or oxalyl chloride, with the optionaladdition of DMF (Hamuro et al. J. Am. Chem. Soc. 1996, 118(32),7529-41). In instances where the carboxylic acid is not commerciallyavailable, it may be prepared by standard methods (Buerstinghaus et al.EP 203607, Dec. 3, 1986; Cai et al J. Chem. Soc. Perkin Trans. I 1997,16, 2273-74; von Geldern et al J. Med. Chem. 1999, 42(18), 3668-78) suchas oxidation of a suitable precursor, such as the correspondinghydroxymethyl-, or methyl-substituted compound (i.e., A-CH₂OH or A-CH₃),carboxylation of the corresponding halo compound (i.e., A-Cl, A-Br, orA-I) using palladium catalaysts, or quenching of a Grignard reagent(prepared from the corresponding halo compound (A-Cl, A-Br, or A-I) withcarbon dioxide.

The Formula 2 product of may then be cyclized to the heterocycle ofFormula 3 in the presence of a base such as aqueous sodium hydroxide,and is facilitated by heating to a temperature sufficient to effect thecyclization, typically, 40-95° C. In the instance where compound is anitrile, the reaction mixture also contains H₂O₂ (usually in about 3-30%concentration), or alternatively, is conducted in 0.1 to 3.0 N mineralacid. The compound of Formula 3 is then converted to a compound ofFormula 4 by treatment with a reagent such as SOCl₂, POCl₃/PCl₅, POCl₃,POBr₃ or P₂S₅/Et I (two steps) and is facilitated by the addition of acatalytic amount of DMF and heating. The compound of Formula 4 is thenallowed to react in a water-miscible solvent such as DME, THF or DMF,with the amino heterocycle of Formula 5, in the presence of a base suchas sodium or potassium acetate, potassium carbonate; or in dilute (0.1M)hydrochloride acid, and water and with heating sufficient to effectreaction. In cases where the starting material 4 is especially labile,undesired side reactions (e.g., hydrolysis of 4 to 3 are minimized byreducing the amount of water added to water-miscible cosolvent to theminimum amount required to achieve dissolution and reaction.

It is to be understood that the specific conditions selected from thisGeneral Method will depend on the particular structures of the startingmaterials chosen, in order to optimize the yield of the productsdesired.

In Formula I, suitable aryl or heteroaryl groups, e.g., for A, include,but are not limited to, 5-12 carbon-atom aromatic rings or ring systemscontaining 1-3 rings, at least one of which is aromatic, in which one ormore, e.g., 1-4 carbon atoms in one or more of the rings can be replacedby oxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms.For example, aryl or heteroaryl can be 2- or 3-furyl, 2- or 3-thienyl,2- or 4-triazinyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-,3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-,4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-,4-, 5- or 6-pyrimidinyl, 1,2,3-triazol-1-, -4- or 5-yl,1,2,4-triazol-1-, -3- or B5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4-or 5-yl, 1,2,4-oxadiazol-3- or 5-yl, 1,3,4-thiadiazol-2- or 5-yl,1,2,4-oxadiazol-3- or 5-yl, 1,3,4-thiadiazol-2- or 5-yl,1,3,4-thiadiazol-3- or 5-yl, 1,2,3-thiadiazol-4- or 5-yl, 2-, 3-, 4-, 5-or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl,pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5-6- or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 2-, 4-, 5-,6- or 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl,1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl,1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, or 2-, 4-, 5-, 6-, 7- or8-quinazolinyl, or additionally optionally substituted phenyl, 2- or3-thienyl, 1,3,4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl, 2-thiazolyl or5-thiazolyl, etc.

Preferred moieties A include cyclohexyl; or C₅₋₁₂-aryl orC₅₋₁₂-heteroaryl each independently optionally substituted up to threetimes by (i) C₁-C₁₀-alkyl or C₂₋₁₀-alkenyl each optionally substitutedwith halogen up to perhalo; (ii) C₃-C₁₀ cycloalkyl; (iii) C₅₋₁₂-aryloptionally substituted by 1-3 halogen atoms; (iv) C₅₋₁₂-heteroaryl; (v)halogen; (vi) —CO—OR₈; (vii) —CO—R₈; (viii) cyano; (ix) —OR₈; (x)—NR₈R₁₃; (xi) nitro; (xii) —CO—NR₈R₉; (xiii) —C₁₋₁₀-alkyl-NR₈R₉; (xiv)—NR₈—CO—R₁₂; (xv) —NR₈—CO—OR₉; (xvi) —NR₈—SO₂—R₉; (xvii) —SR₈; (xviii)—SO₂—R₈; (xix) —SO₂—NR₈R₉, or (xx) NR₈—CO—NHR₉.

Further preferred moieties A include phenyl, pyridyl, pyrimidinyl,oxazolyl, furyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl andpyrazinyl, each independently substituted up to three times by halogen,C₁₋₁₀-alkyl, C₁₋₁₀-alkoxyphenyl, naphthyl, —OR₁₀,

wherein each Z independently is halogen, hydroxy, hydroxy-C₁₋₁₀-alkyl,—CN, —NO₂, C₁₋₁₀-alkoxycarboxyl, —NR₁₀—CO—R₁₁, or —NR₁₀—CO—OR₁₁,y is 1-3,and R₄ is as described above.

Preferred moieties A additionally include

wherein R₁₅ is H; phenyl optionally substituted by C₁₋₁₀-alkyl,C₁₋₁₀-alkoxy, C₁₋₁₀-alkylcarboxyl, or halogen; benzyl; pyrimidyl orpyridyl; and R₁₆ is H, phenyl, —COOR₁₀,

The terms identified above have the following meaning throughout:

“C₁₋₆ alkyl” means straight or branched chain alkyl groups having fromone to about six carbons. Such groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,neo-pentyl, 2-pentyl, n-hexyl, 2-hexyl, 3-hexyl, 2,3-dimethylbutyl, andthe like.

“C₁₋₁₀ alkyl” means straight or branched chain alkyl groups having fromone to about ten carbon atoms.

“C₃₋₈ cycloalkyl” means saturated monocyclic alkyl groups of from 3 toabout 8 carbon atoms and includes such groups as cyclopropyl,cyclopentyl, cyclohexyl, and the like.

“C₃₋₁₀cycloalkyl” means saturated monocyclic alkyl groups of from 3 toabout 10 carbon atoms.

“C₁₋₆ alkoxy” means straight or branched chain alkoxy groups having fromone to about six carbon atoms and includes such groups as methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,tert-butoxy, and the like.

“Halo” means fluoro, chloro, bromo, or iodo.

“Mineral Acid” means hydrochlorine acid, sulfuric acid, nitric acid, andthe like.

When an alkyl, cycloalkyl, alkenyl, or alkoxy group is described asbeing substituted with fluoro, it may be substituted with one or morefluorine atoms at any available carbon atom up to the perfluoro level.

When an alkyl substituent is described as being substituted by oxo, itmeans substitution by a doubly bonded oxygen atom, which forms togetherwith the carbon to which it is attached, a carbonyl group —(C═O)—.

When any moiety is described as being substituted, it can have one ormore of the indicated substituents that can be located at any availableposition on the moiety. When there are two or more substituents on anymoiety, each substituent is defined independently of any othersubstituent and can, accordingly, be the same or different.

The term “optionally substituted” means that the moiety so modified maybe unsubstituted or substituted with the identified substituent(s).

R₅ may be attached to the benzo moiety of the compounds of Formulas 1,2, 3, 4, or (I), at any available carbon atom and when there are two ormore R₅ substituents (i.e., p=2 or 3), each substituent is definedindependently of other substituents and can, accordingly be the same ordifferent.

“Aqueous Hydroxide” Means an Aqueous Solution Containing Off, UsuallyPrepared from a1

“Water-miscible cosolvent” means an organic solvent which is at leastpartially miscible with water at a temperature in which the reaction iscarried out. Such solvents include but are not limited to alcohols suchas methanol, ethanol, isopropanol, butanol, methoxyethanol and the like,ethers such as dimethoxyethane (DME), tetrahydrofuran (THF), dioxane andthe like, non-protic solvents such as N,N-dimethylformamide (DMF), anddimethylsulfoxide (DMSO), and solvents which may form an azeotrope withwater such as toluene.

“Non-nucleophilic amine base” means a base capable of reacting with orneutralizing an acid, without the tendency to undergo nucleophilicsubstitution reactions. Such bases include diazabicycloundecane,4-dimethylaminopyridine,

“Non-protic solvent” means a solvent that does not readily dissociate toprovide a H⁺ ion, i.e. contains no H atoms with a pKa of less than about20. Examples of such solvents include dimethylformamide DMF, THF, ether,toluene, benzene, dimethoxyethane (DME), diglyme, dioxane,

Sensitive or reactive substituents, on the compounds of Formulas 1, 2,3, 4, 5 or (I) may need to be protected and deprotected during any ofthe above methods of preparation. Protecting groups in general may beadded and removed by conventional methods well known in the art (see,e.g., T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis; Wiley: New York, (1999)).

The present invention is also directed to the production ofpharmaceutically acceptable salts of compounds of Formula I. Suitablepharmaceutically acceptable salts are well known to those skilled in theart and include basic salts of inorganic and organic acids, such ashydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, sulphonic acid, acetic acid, trifluoroaceticacid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid,succinic acid, fumaric acid, maleic acid, benzoic acid, salicyclic acid,phenylacetic acid, and mandelic acid. In addition, pharmaceuticallyacceptable salts include acid salts of inorganic bases, such as saltscontaining alkaline cations (e.g., Li⁺, Na⁺ or K⁺), alkaline earthcations (e.g., Mg⁺, Ca⁺ or Ba⁺), the ammonium cation, as well as acidsalts of organic bases, including aliphatic and aromatic substitutedammonium, and quaternary ammonium cations, such as those arising fromprotonation or peralkylation of triethylamine, N,N-diethylamine,N,N-dicyclohexylamine, pyridine, N,N-dimethylaminopyridine (DMAP),1,4-diazabiclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene(DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Preparation of suchsalts can proceed via a final conventional step using a compound ofFormula I, subsequent to the above preparation process.

ABBREVIATIONS AND ACRONYMS

When the following abbreviations are used herein, they have thefollowing meaning:

-   Ac₂O acetic anhydride-   anhy anhydrous-   n-BuOH n-butanol-   t-BuOH t-butanol-   CD₃OD methanol-d₄-   Celite® diatomaceous earth filter agent,® Celite Corp.-   CH₂Cl₂ methylene chloride-   CI-MS chemical ionization mass spectroscopy-   conc concentrated-   dec decomposition-   DME dimethoxyethane-   DMF N,N-dimethylformamide-   DMSO dimethylsulfoxide-   ELSD evaporative light scattering detector-   EtOAc ethyl acetate-   EtOH ethanol (100%)-   Et₂O diethyl ether-   Et₃N triethylamine-   HPLC ES-MS high performance liquid chromatography-electrospray mass    spectroscopy-   NMM 4-methylmorpholine-   Ph₃P triphenylphosphine-   Pd(dppf)Cl_(2 [)1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-   Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium(0)-   Pd(OAc)₂ palladium acetate-   P(O)Cl₃ phosphorous oxychloride-   RT retention time (HPLC)-   rt room temperature-   THF tetrahydrofuran-   TFA trifluoroacetic acid-   TLC thin layer chromatography

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the foregoing and in the following examples, all temperatures are setforth uncorrected in degrees Celsius and, all parts and percentages areby weight, unless otherwise indicated.

The entire disclosure of all applications, patents and publications,cited above or below, and of U.S. Provisional Application No.60/315,341, filed Aug. 29, 2001 (Attorney Docket No. Bayer-27 V2), U.S.patent application Ser. No. 10/103,566, filed Mar. 22, 2002, U.S. patentapplication Ser. No. 10/103,565, filed Mar. 22, 2002, PCT ApplicationNo. PCT/US02/08659, filed Mar. 22, 2002, and PCT Application No.PCT/US02/08660, filed Mar. 22, 2002, are hereby incorporated byreference.

EXAMPLES Example 1 Preparation of 3-fluoro-4-phenylbenzoic acid

A suspension of magnesium (0.968 g, 3.98 mmol) and a few crystals ofiodine in anhyd THF (200 mL) were treated with dropwise addition of 10mL of a solution of 4-bromo-2-fluorobiphenyl (10.0 g, 3.98 mmol) in THF(100 mL). The mixture was heated to gentle reflux and a reaction ensued.At that time, the remaining solution of 4-bromo-2-fluorobiphenyl wasadded dropwise to the flask over a 3-minute period. The contents werethen stirred at reflux under argon until no magnesium consumption wasobserved. The reaction mixture was subsequently cooled to −10° C. andtreated with dry ice (˜70 g). The reaction mixture was quenched with 20%aqueous hydrochloric acid (50 mL), and the layers were separated. Theaqueous phase was extracted with ethyl acetate (2×20 mL), and thecombined organic layer was washed with brine (30 mL), dried over anhydsodium sulfate and concentrated to about ⅓ of its original volume. Thecontents were treated with hexane (200 mL), and the precipitate wasfiltered and dried under high vacuum to afford 3-fluoro-4-phenylbenzoicacid (6.37 g, 74%) as a white, crystalline solid. ¹H-NMR (DMSO-d₆): δ7.48 (m, 3H); 7.59 (m, 2H); 7.66 (dd, J=8.1, 8.1 Hz, 1H); 7.76 (dd,J=1.5, 11.6 Hz, 1H); 7.85 (dd, J=1.5, 8.1 Hz, 1H); 13.30 (br s, 1H).Anal. Calcd for C₁₃H₉FO₂: C, 72.22; H, 4.20; F, 8.79. Found: C, 71.95;H, 4.11; F, 9.07.

Example 2 Preparation of2[(3-fluoro-4-phenylphenyl)carbonylamino]benzamide

A suspension of the product of step 1 (0.5 g, 2.31 mmol) in oxalylchloride (5 mL) was treated with one drop of DMF and the mixture washeated to 60° C. for 45 min. The resulting, clear-yellow solution wasconcentrated to a yellow solid, which was dried under high vacuum for 60min. The solid and anthranilamide (0.314 g, 2.31 mmol) were suspended indry toluene (5 mL), treated with diisopropylethylamine (0.5 ml, 0.371 g,2.87 mmol) and the contents were stirred at room temperature for 2 h, atwhich time TLC (silica gel 60, 10% methanol/dichloromethane, UVdetection) analysis suggested complete reaction. The mixture wasfiltered, and the off-white solid was dissolved in ethyl acetate (50mL). The organics were washed with brine (25 mL), 0.1 N aqueoushydrochloric acid (25 mL), and again with brine (25 mL). The organiclayer was dried over anhyd sodium sulfate, concentrated and dried underhigh vacuum for 4 h to afford the product (0.59 g, 1.76 mmol, 76%) as anoff-white solid. ¹H-NMR (DMSO-d₆): δ 7.22 (ddd, J=1.2, 7.4, 7.8 Hz, 1H);7.52 (m, 6H); 7.78 (m, 3H); 7.89 (m, 1H); 7.89, 8.47 (br s, 2H); 8.69(dd, J=1.2, 8.3 Hz, 1H); 13.12 (s, 1H). Anal. Calcd for C₂₀H₁₅N₂FO₂: C,71.85; H, 4.52; N, 8.38. Found: C, 71.67; H, 4.47; N, 8.35. Massspectrum (HPLC/ES, flow injection): m/e=335 (M+1).

Example 3 Preparation of2-(3-fluoro-1,1′-biphenyl-4-yl)-4(3H)-quinazolinone

Method A (One Pot)

A suspension of the product of Example 1 (0.5 g, 2.31 mmol) in oxalylchloride (5 mL) was treated with one drop of DMF and the mixture washeated to 60° C. for 60 min. The resulting clear yellow solution wasconcentrated to a yellow solid, which was dried under high vacuum for 2h. This solid and anthranilamide (0.314 g, 2.31 mmol) were dissolved indry THF (5 mL), treated with diisopropylethylamine (0.5 ml, 0.371 g,2.87 mmol) and the contents were stirred at room temperature for 90 min,at which time TLC (silica gel 60, 5% methanol/dichloromethane, UVdetection) analysis suggested complete reaction. The mixture was treatedwith aqueous 1.0 N sodium hydroxide (10.0 mL, 10.0 mmol). The contentswere heated to 50° C. (complete dissolution occurred when the internaltemperature reached 44° C.) for 90 min and the organic solvent wasremoved by rotary evaporation. The aqueous suspension was treated withdropwise addition of aqueous 2.0 N hydrochloric acid (about 5 mL) untilthe pH was adjusted to about 2. The precipitate was filtered and thecake was washed with water (4×30 mL) and dried under high vacuum at 40°C. for 18 h to provide the product (0.67 g, 2.12 mmol, 92%) as a whitepowder. ¹H-NMR (DMSO-d₆): δ 7.52 (m, 4H); 7.64 (m, 2H); 7.75 (m, 2H);7.86 (ddd, J=1.4, 6.9, 8.0 Hz, 1H); 8.16 (m, 3H); 12.63 (br s, 1H).Anal. Calcd for C₂₀H₁₃N₂FO: C, 75.94; H, 4.14; N, 8.86. Found: C, 75.66;H, 4.29; N, 8.77. Mass spectrum (HPLC/ES): m/e=317 (M+1).

Method B

A suspension of the product of Example 1 (0.5 g, 2.31 mmol) in oxalylchloride (5 mL) was treated with one drop of DMF and the mixture washeated to 60° C. for 60 min. The resulting clear yellow solution wasconcentrated to a yellow solid, which was dried under high vacuum for 60min. This solid and anthranilamide (0.314 g, 2.31 mmol) were suspendedin dry toluene (5 mL), treated with diisopropylethylamine (0.5 ml, 0.371g, 2.87 mmol) and the contents were stirred at room temperature for 2 h,at which time TLC (silica gel 60, 10% methanol/dichloromethane, UVdetection) analysis suggested complete reaction. The mixture wasfiltered and dried under high vacuum for 2 h. The off-white solid wasthen dissolved in methanol (10 mL) and THF (5 mL), and the solution wastreated with aqueous 1.0 N sodium hydroxide (10.0 mL, 10.0 mmol). Thecontents were heated to 45° C. for 2 h and the organic solvents wereremoved by rotary evaporation. The aqueous suspension was treated withdropwise addition of aqueous 2.0 N hydrochloric acid until the pH wasadjusted to about 2 (5 mL). The precipitate was filtered and the cakewas washed with water (4×30 mL) and dried under high vacuum at 40° C.for 3 h to provide product (0.66 g, 2.09 mmol, 90%) as a white powder.¹H-NMR (DMSO-d₆): δ 7.52 (m, 4H, aromatic); 7.64 (m, 2H, aromatic); 7.75(m, 2H); 7.86 (ddd, J=1.4, 6.9, 8.0 Hz, 1H, aromatic); 8.16 (m, 3H,aromatic); 12.63 (br s, 1H, —NH). Anal. Calcd for C₂₀H₁₃N₂FO•0.20H₂O: C,75.08; H, 4.22; N, 8.76. Found: C, 75.08; H, 4.03; N, 8.67. Massspectrum (HPLC/ES): m/e=317 (M+1).

Method C

A solution of the compound of Example 2 (24.10 g, 72.08 mmol) inmethanol (100 mL) and tetrahydrofuran 200 mL) was treated with aqueous1.0 N sodium hydroxide (240 mL, 240 mmol), and the contents were stirredat 40° C. for 60 minutes, at which time TLC (silica gel 60, 10%methanol/dichloromethane, UV detection) analysis suggested completereaction. The organic solvents were rotary evaporated and the aqueousphase was treated with dropwise addition of concentrated hydrochloricacid until the pH was adjusted to 7. The resultant white precipitate wasfiltered, washed with water (2×200 mL) and dried under high vacuum atroom temperature for 2 days and at 45° C. for 2 hours to afford theproduct (21.60 g, 68.28 mmol, 95%) as a white powder. ¹H-NMR (DMSO-d₆):δ 7.50 (m, 4H, aromatic); 7.64 (m, 2H, aromatic); 7.74 (m, 2H); 7.86(ddd, J=1.4, 6.9, 8.0 Hz, 1H, aromatic); 8.16 (m, 3H, aromatic); 12.63(br s, 1H, —NH). Mass spectrum (HPLC/ES): m/e=317 (M+1).

Method D

Step 1. Preparation ofN-(2-cyanophenyl)(3-fluoro-4-phenylphenyl)carboxamide

A suspension of the compound of Example 1 (0.5 g, 2.31 mmol) in oxalylchloride (5 mL) was treated with one drop of N,N-dimethylformamide andthe mixture was heated to 60° C. for 45 minutes. The resultant,clear-yellow solution was concentrated to a yellow solid, which wasdried under high vacuum for 60 minutes. The solid and anthranilonitrile(13, 0.273 g, 2.31 mmol) were suspended in dry toluene (5 mL), treatedwith diisopropylethylamine (0.5 mL, 0.371 g, 2.87 mmol) and the contentswere stirred at room temperature for 6 hours, at which time TLC (silicagel 60, 10% methanol/dichloromethane, UV detection) analysis suggestedcomplete reaction. The mixture was filtered, and the white, crystallinesolid was dissolved in 20% ethyl acetate/dichloromethane (25 mL). Theorganics were washed with 0.1 N aqueous hydrochloric acid (10 mL) andthen with brine (2×25 mL). The organic layer was dried over sodiumsulfate, concentrated and dried under high vacuum at 35° C. for 16 hoursto afford 22 (0.49 g, 1.55 mmol, 67%) as a fluffy, white solid. ¹H-NMR(DMSO-d₆): δ 7.50 (m, 4H, aromatic); 7.62 (m, 3H, aromatic); 7.76 (m,2H, aromatic); 7.92 (m, 3H, aromatic); 10.76 (s, 1H, —NH). Anal. Calcdfor C₂₀H₁₃N₂FO: C, 75.94; H, 4.14; N, 8.86. Found: C, 75.71; H, 4.20; N,8.92. Mass spectrum (HPLC/ES, flow injection): m/e=317 (M+1).

Step 2. A sample of the product of step 1 (0.050 g, 0.158 mmol) wasstirred in 1.5 M hydrochloric acid in ethanol (5 mL) at 40° C. for 60minutes, at which time, TLC (silica gel 60, 20% EtOAc/hexane, UVdetection) analysis indicated complete reaction. The contents wereconcentrated and then taken up in absolute ethanol (5 mL). Thesuspension was stirred, concentrated and the process was repeated twoadditional times. The material was dried under high vacuum at 45° C. for2 hours to afford the product (0.047 g, 0.149 mmol, 94%) as a whitepowder. NMR analysis (see above) suggested that the compound was pure.

Example 4 Preparation of 4-chloro-2-(3-fluoro-4-phenylphenyl)quinazoline

A solution of phosphorous oxychloride (3.0 mL) and anhyd DMF (2 mL) wasstirred for 10 min before it was added to a flask containing the productof step 3 (0.300 g, 0.948 mmol). The resulting suspension was heated togentle reflux under argon for 12 h. The dark solution was then cooled to70° C. and slowly added to vigorously-stirred water (100 mL) at 0° C. Asolid precipitated, which was stirred for 10 min and filtered. The cakewas washed with water (2×25 mL) and dried under high vacuum at 35° C.for 2 h to provide product (0.285 g, 0.851 mmol, 90%) as a yellow solid.Part of this solid (0.125 g) was passed through a short plug of silicagel using 20% dichloromethane/hexane as eluant to afford the titlecompound (0.09 g) as white needles. ¹H-NMR (DMSO-d₆): δ 7.47 (m, 1H);7.54 (m, 2H); 7.65 (m, 2H); 7.76 (dd, J=8.4, 8.4 Hz, 1H); 7.87 (ddd,J=2.9, 5.3, 8.3 Hz, 1H); 8.15 (m, 2H); 8.26 (m, 1H); 8.28 (m, 1H); 8.38(dd, J=1.9, 8.4 Hz, 1H). Anal. Calcd for C₂₀H₁₂N₂ClF: C, 71.75; H, 3.61;N, 8.37; Cl, 10.59. Found: C, 71.54; H, 3.48; N, 8.29; Cl, 10.61. Massspectrum (HPLC/ES): m/e=335 (M+1). TLC (silica gel 60, 40%dichloromethane/hexane, UV detection): one spot, R_(f)=0.50.

Example 5 Preparation of1H-indazol-5-yl[2-(3-fluoro-4-phenylphenyl)quinazolin-4-yl]amine

To a suspension of the product of step 4 (1.00 g, 2.99 mmol) and5-aminoindazole (0.44 g, 3.29 mmol) in ethylene glycol dimethylether(DME, 10 mL) was added a solution of potassium acetate (0.44 g,4.48 mmol) in water (2 mL). The contents were allowed to reflux for 16 hand then cooled to room temperature. The mixture was poured into water(200 mL) and the precipitate was filtered, washed with water (2×50 mL)and air-dried for 60 min. The solid was dissolved in THF (30 mL), andthe solution was slowly poured into hexane (500 mL). The resultingprecipitate was filtered and dried under high vacuum at 60° C. for 18 hto afford the product (1.02 g, 2.36 mmol, 79%) as a yellow solid. ¹H-NMR(DMSO-d₆): δ 7.46 (m, 3H, aromatic); 7.63 (m, 5H, aromatic); 7.83 (dd,J=1.9, 9.0 Hz, 1H, aromatic); 7.87 (m, 2H, aromatic); 8.13 (br s, 1H,—N═CH—); 8.17 (dd, J=1.6, 12.5 Hz, 1H, aromatic); 8.22 (d, J=1.9 Hz, 1H,aromatic); 8.30 (dd, J=1.6, 8.0 Hz, 1H, aromatic); 8.58 (br d, J=8.5 Hz,1H, aromatic); 10.04 (s, 1H, —NH); 13.13 (br s, 1H, —NH). Mass spectrum(HPLC/ES): m/e=432 (M+1).

In order to prepare the p-toluene sulfonic acid (tosylate) salt, asuspension of the product (0.60 g, 1.39 mmol) in anhyd ethanol (12 mL)was treated with a solution of p-toluenesulfonic acid monohydrate (0.39g, 2.09 mmol) in ethanol (8.5 mL) in one portion. The contents werestirred at 40° C. for 60 min and the precipitate was filtered. The cakewas washed with ethanol (3×15 mL) and dried under high vacuum at 40° C.for 18 h to give the tosylate salt (0.71 g, 85%) as a pale-orange,crystalline solid. ¹H-NMR (DMSO-d₆): δ 2.27 (s, 3H); 7.09, 7.47 (AA′BB′quartet, J=8.6 Hz, 4H); 7.48 (m, 2H); 7.52 (m, 2H); 7.62 (m, 2H); 7.73(m, 2H); 7.84 (m, 2H); 8.10 (m, 5H); 8.20 (s, 1H); 8.74 (br d, J=8.4 Hz,1H); 11.50 (br s, 1H). Anal. Calcd for C₂₇H₁₈N₅F•CH₃C₆H₄SO₃H: C, 67.65;H, 4.34; N, 11.60. Found: C, 67.35; H, 4.46; N, 11.49. Mass spectrum(HPLC/ES): m/e=432 (M+1).

Example 6 Preparation ofN-[2-(aminocarbonyl)phenyl]-2,3-dihydro-1-benzofuran-5-carboxamide

A mixture of 2,3-dihydrobenzo[b]furan-5-carboxylic acid (1.0 g, 6.1mmol) in thionyl chloride (2.2 mL, 30.5 mmol) is stirred at roomtemperature for 4 h. The volatiles were removed by evaporation. To asolution of the residue and anthranilamide (750 mg, 5.5 mmol) in CHCl₃(30 mL) is added pyridine (670 L, 8.3 mmol) and the mixture stirred atroom temperature for 18 h. The volatiles were removed by evaporation andthe residue is partitioned between EtOAc and 1 N sodium carbonate. Theresulting precipitate that formed between the aqueous and organic phasesis collected by filtration and dried under vacuum to afford the desiredintermediate (1.5 g, 5.3 mmol; 87% yield);); R_(f)=0.31 (EtOAc/hexanes,95/5); mp=230-235° C.; ES MS (M+H)⁺=283

Example 7 Preparation of2-(2,3-dihydro-1-benzofuran-5-yl)-4-quinazolinol

To a solution of diamide from Step 1 (1.0 g, 3.5 mmol) in EtOH (25 mL)is added 10 N NaOH (1.06 mL, 10.6 mmol). The reaction heated to refluxfor 16 h, the mixture is cooled to room temperature and the volatileswere evaporated. The aqueous mixture is adjusted to pH=5 with conc HCl.The resulting precipitate is collected by filtration and dried undervacuum to afford the desired product: Rf=0.45 (EtOAc/hexanes, 95/5);(856 mg, 3.2 mmol; 91% yield); mp=289-294° C.; ES MS (M+H)⁺=265.

Example 8 Preparation of4-chloro-2-(2,3-dihydro-1-benzofuran-5-yl)quinazoline

To a suspension of material from Step 2 (300 mg, 1.1 mmol) in CHCl₃ (12mL) is added thionyl chloride (990 L, 13.6 mmol) and DMF (20 L, 0.3mmol). The mixture heated to reflux for 4 h, cooled to room temperature,and the volatiles were evaporated. The residue is dried under vacuum toafford the desired intermediate (285 mg, 1.0 mmol; 89% yield); Rf=0.52(EtOAc/hexanes, 80/20); mp=186-192° C.; ES MS (M+H)⁺=283.

Example 9 Preparation of2-(2,3-dihydro-1-benzofuran-5-yl)-N-(1H-indazol-5-yl)-4-quinazolinamine

A mixture of Step 3 compound (100 mg, 0.35 mmol), 5-aminoindazole (47.1mg, 0.35 mmol) and 0.1 M aqueous HCl (350 L) heated at refluxtemperature 16 h. The reaction cooled to room temperature and thesolvent is evaporated in vacuo. The residue is triturated with MeOH anddried under vacuum to afford the product (43.4 mg, 0.11 mmol; 32%yield); Rf=0.57 (CH₂Cl₂/MeOH, 90/10); mp=267-272° C.; ES MS (M+H)⁺=380.

Examples 10-11

By following a procedure analogous to that described for Example 6-9 andusing the appropriate chloroquinazoline and 5-aminoindazole as startingmaterials, the compounds described in Table 1 were similarly prepared:

TABLE 1

Weight obtained Ex. No. A (mg) Yield % Note 10 cyc-Pr 104.6 71 25 11 CF₃ 44.2 31 26 Notes: 25 Rf = 0.46 (CH₂Cl₂/MeOH, 90/10); mp = 272-277° C.;ES MS (M + H)⁺ = 302. 26 Rf = 0.62 (CH₂Cl₂/MeOH, 90/10); mp = 311-319°C.; ES MS (M + H)⁺= 330.

Example 12 Preparation ofN-(1H-indazol-5-yl)-2-(2-quinoxalinyl)-4-quinazolinamine

Step 1: To a solution of anthranilonitrile (7.58 mmol) in dry pyridine(30 mL) is added 2-quinoxaloyl chloride (9.11 mmol, 1.2 equivalent). Thereaction mixture stirred at room temperature overnight and sodiumhydroxide solution (2%, 50 mL) is added. The mixture is cooled andstirred for 30 min. The resulting white solid is collected byfiltration, washed with brine and cold ether. A white solid product isobtained (1.51 g, 73%). HPLC/MS: (M+H)⁺=275, RT (HPLC/MS)=3.0 min.

Step 2: The amide prepared in Step 1 (9.5 mmol, 1 equiv) is suspended indioxane (10 mL). NaOH solution (20%, 60 mL) and hydrogen peroxidesolution (30%, 30 mL) is added in three portions. A vigorous release ofgas is observed. The reaction mixture continued to stir and is cooledwhen necessary until the evolution of gas ceased. The reaction isbrought to 120° C. (oil bath) and stirred overnight at this temperature.The reaction is neutralized with concentrated HCl to pH=7. A precipitateformed and is collected on a funnel, washed with water and dried invacuo. A yellow solid is obtained and used in the next step withoutfurther purification. HPLC/MS: (M+H)⁺=275, RT (HPLC/MS)=3.28.

Step 3: The quinazoline (10.9 mmol) is suspended in phosphorousoxychloride (214.6 mmol) containing PCl₅ (10.9 mmol) and stirred at 115°C. for 18 h. The resulting yellow solution is poured into 300 mL of iceand stirred. A gray precipitate formed and filtered and washed with coldwater. The product is used in the next step without furtherpurification. HPLC/MS: (M+H)⁺=293, RT (LC-MS)=3.40.

Step 4: A mixture of 4-chloroquinazoline, potassium acetate (14.25mmol), and 5-aminoindazole (10.96 mmol) in THF/H₂O (70 mL/25 mL) isstirred at room temperature for 17 h. The resulting solid is collectedby filtration and purified by silica gel column chromatography(gradient, 5-10% MeOH/CH₂Cl₂) to afford the product (1.19 g, 32%, 3steps) as yellow powder. HPLC/MS: (M+H)⁺=390, RT (LC-MS)^(,) 2.41.

Example 13 Preparation of5-Fluoro-N-(1H-indazol-5-yl)-2-(2-methylphenyl)-4-quinazolinamine

Step 1: To a solution of 6-fluoro-2-amino-benzonitrile (2 mmol, 1equivalent.) in pyridine (3 mL) and CH₂Cl₂ (1 mL) containingN-dimethylaminopyridine (3 mg) is added 2-toluoyl chloride (316 mL, 1.2equivalent). The reaction mixture is shaken at room temperature for 48 hand poured into cold water (3 mL) and shaken for 1 h. The resultingsolid is filtered and washed with water to afford a white solid (90%).The LC-MS is consistent with the desired compound.

Step 2: The product is suspended in aqueous NaOH (20%, 2 mL) and dioxane(1 mL). Hydrogen peroxide (30%, 1 mL) is added in potions to avoidvigorous formation of gas. The reaction is shaken at 85° C. for 20 h andthen is neutralized with acetic acid to pH=7. The resulting precipitateis collected by filtration, washed with water and ether, and dried overP₂O₅ for two days. The product is suspended in P(O)Cl₃ (4 mL) and shakenat 90° C. overnight. The POCl₃ is removed in vacuo and co-evaporatedwith toluene. The resulting yellow solid residue is dried in vacuoovernight and used in the next step without further purification

Step 3: The product (assumed to be 2 mmol), 5-aminoindazole (3 mmol, 1.5equiv), and potassium carbonate (2 mmol) were suspended in DMF (5 mL)containing and shaken at 90° C. for 24 h. The reaction suspension isfiltered and the filtrate is purified by HPLC, under the followingconditions:

Column: YMC C18 Pro, 20×150 m/m; Gradient: A=H2O, 0.1% TFA, B=CH₃CN,0.1% TFA; Gradient over 10 min, flow: 30 mL/min. A pale yellow solidproduct is obtained. (M+H)⁺=370, RT (LC-MS)=2.19 min.

Using the method described above for Example 13 and substituting theappropriate starting materials, the compounds listed in Table 2 werealso synthesized.

TABLE 2

Example LC-MS Mass No (R₅) A RT (min) Spec 14 5-F 4-fluorophenyl 2.67374 15 5-F 3-chlorophenyl 3.14 350 16 5-F 4-bromophenyl 3.09 434 17 5-F3-methylphenyl 2.56 370 18 5-F 3-bromophenyl 3.18 434 19 5-F2-chlorophenyl 2.52 390 20 5-F 3-methoxyphenyl 2.52 386 21 5-F2-quinoxalinyl 2.48 408 22 5-F 1-naphthyl 2.48 406 23 5-F 2-naphthyl2.96 406 24 5-F 4-pyridinyl 2.3  357 25 7-methyl 2-quinoxalinyl 2.37 40426 7-methyl 3-chlorophenyl 2.56 386 27 7-methyl 4-fluorophenyl 2.30 37028 7-methyl 4-methylphenyl 2.41 366 29 7-methyl 4-bromophenyl 2.59 43030 7-methyl 4-methoxyphenyl 2.30 382 31 7-methyl 2-methylphenyl 2.26 36632 7-methyl 3-methylphenyl 2.41 366 33 7-methyl 3-fluorophenyl 2.48 37034 7-methyl 3-bromophenyl 2.70 430 35 7-methyl 2-chlorophenyl 2.37 38636 7-methyl 3-methoxyphenyl 2.44 382

Example 37 Preparation of4-ethylthio-2-(3-fluoro-4-phenylphenyl)quinazoline

A mixture of Example 3 (2.0 g, 6.32 mmol) and phosphorous pentasulfide(0.560 g, 2.53 mmol) in pyridine (20 mL) was heated to 114° C. for 5 h,at which time TLC (silica gel 60, 10% MeOH/dichloromethane, UVdetection) analysis indicated complete reaction. The contents werecooled to 60° C. and slowly added to vigorously-stirred water (50 mL) at40° C. The mixture was stirred for 20 minutes, filtered and dried underhigh vacuum to provide2-(3-fluoro-1,1′-biphenyl-4-yl)-4(3H)-quinazolinethione, 2.05 g, 6.17mmol, 98%) as a yellow solid. A suspension of this material (0.500 g,1.50 mmol) in dimethyl sulfoxide (4 mL) was treated with iodoethane(0.26 mL, 0.0507 g, 3.25 mmol) in one portion, followed by dropwiseaddition of aqueous sodium bicarbonate (1.6 mL). The mixture was stirredat room temperature for 16 hours, slowly poured into vigorously-stirredwater (30 mL) and filtered. The resultant cake was dried under highvacuum at 40° C. for 15 hours to afford4-ethylthio-2-(3-fluoro-4-phenylphenyl)quinazoline (0.471 g, 1.31 mmol,87%) as a pale-yellow solid. ¹H-NMR (DMSO-d₆): δ 1.48 (t, J=7.4 Hz, 3H,—CH₂CH₃); 3.51 (q, J=7.4 Hz, 2H, —CH₂CH₃); 7.50 (m, 3H, aromatic); 7.69(m, 4H, aromatic); 7.99 (m, 2H, aromatic); 8.09 (m, 1H aromatic); 8.33(dd, J=1.7, 12.3 Hz, 1H, aromatic); 8.45 (dd, 1H J=1.7, 8.0 Hz,aromatic). Mass spectrum (HPLC/ES): m/e=361 (M+1).

Example 38 Preparation of1H-indazol-5-yl[2-(3-fluoro-4-phenylphenyl)quinazolin-4-yl]amine fromExample 37

A solution of 5-aminoindazole (0.020 g, 0.15 mmol) in dryN,N-dimethylformamide (4 mL) was added dropwise to a solution ofpotassium t-butoxide (0.017 g, 0.15 mmol) in dry N,N-dimethylformamide(1 mL). The reaction mixture went from green to red within a 20-minuteperiod, and the contents were stirred at room temperature for 1 hourbefore the flask was treated with a solution of the compound of Example37 (0.050 g, 0.14 mmol) in dry N,N-dimethylformamide (2 mL). Thecontents were stirred at room temperature for 2 hours, at which time TLC(silica gel 60, 5% methanol/dichloromethane, UV detection) analysisindicated complete consumption of starting quinazoline. The reactionmixture was poured into ethyl acetate (20 mL), and the organics werewashed with brine (20 mL, 3×30 mL), dried over sodium sulfate andconcentrated. The material was air-dried for 2 hours to give the product(0.031 g, 51%) as a pale-green solid. The NMR data was identical to thatobtained in Example 5.

The entire disclosure of all applications, patents and publications,cited above or below, corresponding U.S. Provisional Application Ser.No. 60/277,974, filed Mar. 23, 2001, U.S. Provisional Applications60/315,341, filed Aug. 29, 2001, U.S. Provisional Application Ser. No.60/315,388, filed Aug. 29, 2001, U.S. application Ser. No. 10/103,565,filed Mar. 22, 2002, U.S. application Ser. No. 10/103,566, filed Mar.22, 2002, International Patent Application No. PCT/US02/08659 filed Mar.22, 2002, and International Patent Application No. PCT/US02/08660 filedMar. 22, 2002, are hereby incorporated by reference.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A process for the preparation of a compound of Formula (I)

comprising reacting a compound of Formula 1

with a compound of Formula

to produce a compound of Formula 2

cyclizing 2 to form a compound of Formula 3

replacing the hydroxy group of 3 with a leaving group to form a compoundof Formula 4′

optionally isolating said compound of Formula 4′; reacting a mixture ofsaid compound of Formula 4′ and a compound of Formula 5

and optionally isolating said compound of Formula (I); wherein inFormulas 3, 4′, 5 and (I) a and c are each independently —CR₅═, —N═, or—NR₆—, wherein one of a or c is —NR₆—; b is —CR₅═ or —N═; A is a 3-20atom, cyclic or polycyclic moiety, e.g., containing 1-4 rings, whichoptionally contain 1-3 N, O or S atoms per ring, and may optionally bearyl or heteroaryl, which cyclic or polycyclic moiety may optionally besubstituted up to 3 times by (i) C₁-C₁₀ alkyl or C₂-C₁₀-alkenyl, eachoptionally substituted with halogen up to perhalo; (ii) C₃-C₁₀cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR₈;(vii) —CO—R₈; (viii) cyano; (ix) —OR₈, (x) —NR₈R₁₃; (xi) nitro; (xii)—CO—NR₈R₉; (xiii) —C₁₋₁₀-alkyl-NR₈R₉; (xiv) —NR₈—CO—R₁₂; (xv)—NR₈—CO—OR₉; (xvi) —NR₈—SO₂—R₉; (xvii) —SR₈; (xviii) —SO₂—R₈; (xix)—SO₂—NR₈R₉; or (xx) NR₈—CO—NHR₉; R₁, and R₆ and R₈-R₁₁ are eachindependently H or C₁₋₆ alkyl; R₂-R₅ are each independently (i) C₁₋₁₀alkyl or C₂₋₁₀-alkenyl each optionally substituted by amino, N-loweralkylamino, N,N-dilower alkylamino, N-lower alkanoylamino, hydroxy,cyano, —COOR₁₀, —COR₁₄, —OCOR₁₄, —OR₁₀, C₅₋₁₀-heteroaryl,C₅₋₁₀-heteroaryloxy, or C₅₋₁₀-heteroaryl-C₁₋₁₀-alkoxy, halogen up toperhalo; (ii) C₃-C₁₀ cycloalkyl, in which 1-3 carbon atoms areoptionally independently replaced by O, N or S; (iii)C₃₋₄₀-cycloalkenyl; (iv) partially unsaturated C₅₋₁₀-heterocyclyl; (v)aryl; (vi) heteroaryl; (vii) halogen; (viii) —CO—OR₁₀; (ix) —OCOR₁₀; (x)—OCO₂R₁₀; (xi) —CHO; (xii) cyano; (xiii) —OR₁₆; (xiv) —NR₁₀R₁₅; (xv)nitro; (xvi) —CO—NR₁₀R₁₁; (xvii) —NR₁₀—CO—R₁₂; (xviii) —NR₁₀—CO—OR₁₁;(xix) —NR₁₀—SO₂—R₁₂; (xx) —SR₁₆; (xxi) —SOR₁₆; (xxii) —SO₂—R₁₆; (xxiii)—SO₂—NR₁₀R₁₁; (xxiv) NR₁₀—CO—NHR₁₁; (xxv) amidino; (xxvi) guanidino;(xxvii) sulfo; (xxviii) —B(OH)₂; (xxix) —OCON(R₁₀)₂; or (xxx)—NR₁₀CON(R₁₀)₂; R₁₂ is H, C₁₋₆-alkyl or C₅₋₁₀-aryl, R₁₃ is H, C₁₋₆-alkylor C₁₋₆-alkoxy, R₁₄ is lower alkyl or phenyl; R₁₅ is lower alkyl,halogen, amino, N-lower alkyl amino, N,N-dilower alkylamino, N-loweralkanoylamino, OH, CN, COOR₁₀, —COR₁₄ or —OCOR₁₄; R₁₆ is hydrogen,C₁₋₆-alkyl optionally substituted by halogen, up to perhalo, orC₅₋₁₀-heteroaryl; and p=0, 1, 2 or 3; LG is Br or S-alkyl; and Q isCONH₂; with the proviso that compound I is not


2. A process for the preparation of a compound of Formula (I)

comprising reacting a compound of Formula 4

and a compound of Formula 5

wherein in Formulas 3, 4, 5 and (I) a and c are each independently—CR₅═, —N═, or —NR₆—, wherein one of a or c is —NR₆—; b is —CR₅═ or —N═;A is a 3-20 atom, cyclic or polycyclic moiety, e.g., containing 1-4rings, which optionally contain 1-3 N, O or S atoms per ring, and mayoptionally be aryl or heteroaryl, which cyclic or polycyclic moiety mayoptionally be substituted up to 3 times by (i) C₁-C₁₀ alkyl orC₂-C₁₀-alkenyl, each optionally substituted with halogen up to perhalo;(ii) C₃-C₁₀ cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi)—CO—OR₈; (vii) —CO—R₈; (viii) cyano; (ix) —OR₈, (x) —NR₈R₁₃; (xi) nitro;(xii) —CO—NR₈R₉; (xiii) —C₁₋₁₀-alkyl-NR₈R₉; (xiv) —NR₈—CO—R₁₂; (xv)—NR₈—CO—OR₉; (xvi) —NR₈—SO₂—R₉; (xvii) —SR₈; (xviii) —SO₂—R₈; (xix)—SO₂—NR₈R₉; or (xx) NR₈—CO —NHR₉; R₁, R₆ and R₈-R₁₁ are eachindependently H or C₁₋₆ alkyl; R₂-R₅ are each independently (i) C₁₋₁₀alkyl or C₂₋₁₀-alkenyl each optionally substituted by amino, N-loweralkylamino, N,N-dilower alkylamino, N-lower alkanoylamino, hydroxy,cyano, —COOR₁₀, —COR₁₄, —OCOR₁₄, —OR₁₀, C₅₋₁₀-heteroaryl,C₅₋₁₀-heteroaryloxy, or C₅₋₁₀-heteroaryl-C₁₋₁₀-alkoxy, halogen up toperhalo; (ii) C₃-C₁₀ cycloalkyl, in which 1-3 carbon atoms areoptionally independently replaced by O, N or S; (iii)C₃₋₄₀-cycloalkenyl; (iv) partially unsaturated C₅₋₁₀-heterocyclyl; (v)aryl; (vi) heteroaryl; (vii) halogen; (viii) —CO—OR₁₀; (ix) —OCOR₁₀; (x)—OCO₂R₁₀; (xi) —CHO; (xii) cyano; (xiii) —OR₁₆; (xiv) —NR₁₀R₁₅; (xv)nitro; (xvi) —CO—NR₁₀R₁₁; (xvii) —NR₁₀—CO—R₁₂; (xviii) —NR₁₀—CO—OR₁₁;(xix) —NR₁₀—SO₂—R₁₂; (xx) —SR₁₆; (xxi) —SOR₁₆; (xxii) —SO₂—R₁₆; (xxiii)—SO₂—NR₁₀R₁₁; (xxiv) NR₁₀—CO—NHR₁₁; (xxv) amidino; (xxvi) guanidino;(xxvii) sulfo; (xxviii) —B(OH)₂; (xxix) —OCON(R₁₀)₂; or (xxx)—NR₁₀CON(R₁₀)₂; R₁₂ is H, C₁₋₆-alkyl or C₅₋₁₀-aryl, R₁₃ is H, C₁₋₆-alkylor C₁₋₆-alkoxy, R₁₄ is lower alkyl or phenyl; R₁₅ is lower alkyl,halogen, amino, N-lower alkyl amino, N,N-dilower alkylamino, N-loweralkanoylamino, OH, CN, COOR₁₀, —COR₁₄ or OCOR₁₄; R₁₆ is hydrogen,C₁₋₆-alkyl optionally substituted by halogen, up to perhalo, orC₅₋₁₀-heteroaryl; and p=0, 1, 2 or 3; LG is Br or S-alkyl; with theproviso that compound I is not


3. A process for the preparation of a compound of Formula 3

from a compound of Formula 2

comprising mixing said compound of Formula 2, where Q is —CO—NH₂, withabout 0.1 N to about 10 N aqueous hydroxide, and heating from atemperature of about 30° C. to about 120° C.; wherein A is a 3-20 atom,cyclic or polycyclic moiety, e.g., containing 1-4 rings, whichoptionally contain 1-3 N, O or S atoms per ring, and may optionally bearyl or heteroaryl, which cyclic or polycyclic moiety may optionally besubstituted up to 3 times by (i) C₁-C₁₀ alkyl or C₂-C₁₀-alkenyl, eachoptionally substituted with halogen up to perhalo; (ii) C₃-C₁₀cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR₈;(vii) —CO—R₈; (viii) cyano; (ix) —OR₈, (x) —NR₈R₁₃; (xi) nitro; (xii)—CO—NR₈R₉; (xiii) —C₁₋₁₀-alkyl-NR₈R₉; (xiv) —NR₈—CO—R₁₂; (xv)—NR₈—CO—OR₉; (xvi) —NR₈—SO₂—R₉; (xvii) —SR₈; (xviii) —SO₂—R₈; (xix)—SO₂—NR₈R₉; or (xx) NR₈—CO —NHR₉; R₅ is (i) C₁₋₁₀ alkyl or C₂₋₁₀-alkenyleach optionally substituted by amino, N-lower alkylamino, N,N-diloweralkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR₁₀, —COR₁₄,—OCOR₁₄, —OR₁₀, C₅₋₁₀-heteroaryl, C₅₋₁₀-heteroaryloxy, orC₅₋₁₀-heteroaryl-C₁₋₁₀-alkoxy, halogen up to perhalo; (ii) C₃-C₁₀cycloalkyl, in which 1-3 carbon atoms are optionally independentlyreplaced by O, N or S; (iii) C₃₋₁₀-cycloalkenyl; (iv) partiallyunsaturated C₅₋₁₀-heterocyclyl; (v) aryl; (vi) heteroaryl; (vii)halogen; (viii) —CO—OR₁₀; (ix) —OCOR₁₀; (x) —OCO₂R₁₀; (xi) —CHO; (xii)cyano; (xiii) —OR₁₆; (xiv) —NR₁₀R₁₅; (xv) nitro; (xvi) —CO—NR₁₀R₁₁;(xvii) —NR₁₀—CO—R₁₂; (xviii) —NR₁₀—CO—OR₁₁; (xix) —NR₁₀—SO₂—R₁₂; (xx)—SR₁₆; (xxi) —SOR₁₆; (xxii) —SO₂—R₁₆; (xxiii) —SO₂—NR₁₀R₁₁; (xxiv)NR₁₀—CO—NHR₁₁; (xxv) amidino; (xxvi) guanidino; (xxvii) sulfo; (xxviii)—B(OH)₂; (xxix) —OCON(R₁₀)₂; or (xxx) —NR₁₀CON(R₁₀)₂; p=0, 1, 2, or 3R₈-R₁₁ are each independently H or C₁₋₆ alkyl R₁₂ is H, C₁₋₆-alkyl orC₅₋₁₀-aryl, R₁₃ is H, C₁₋₆-alkyl or C₁₋₆-alkoxy, R₁₄ is lower alkyl orphenyl; R₁₅ is lower alkyl, halogen, amino, N-lower alkyl amino,N,N-dilower alkylamino, N-lower alkanoylamino, OH, CN, COOR₁₀, —COR₁₄ or—OCOR₁₄; R₁₆ is hydrogen, C₁₋₆-alkyl optionally substituted by halogen,up to perhalo, or C₅₋₁₀-heteroaryl, and wherein Formulas 2 and 3encompass tautomers, optical isomers, or salts thereof.
 4. A process forthe preparation of a compound of Formula 3,

from a carboxylic acid of Formula A-CO₂H and a compound of Formula 1,

comprising in a single vessel, treating said carboxylic acid with achlorinating agent, with optional addition of a catalytic amount of DMF,to form an acid chloride of Formula A-CO—Cl; adding a non-nucleophilicamine base and a non-protic solvent with stirring at room temperature toform a compound of Formula 2;

and adding of a base and heating the mixture up to about 50° C.; for asufficient time to effect reaction; wherein Q is CO—NH₂, A is a 3-20atom, cyclic or polycyclic moiety, e.g., containing 1-4 rings, whichoptionally contain 1-3 N, O or S atoms per ring, and may optionally bearyl or heteroaryl, which cyclic or polycyclic moiety may optionally besubstituted up to 3 times by (i) C₁-C₁₀ alkyl or C₂-C₁₀-alkenyl, eachoptionally substituted with halogen up to perhalo; (ii) C₃-C₁₀cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR₈;(vii) —CO—R₈; (viii) cyano; (ix) —OR₈, (x) —NR₈R₁₃; (xi) nitro; (xii)—CO—NR₈R₉; (xiii) —C₁₋₁₀-alkyl-NR₈R₉; (xiv) —NR₈—CO—R₁₂; (xv)—NR₈—CO—OR₉; (xvi) —NR₈—SO₂—R₉; (xvii) —SR₈; (xviii) —SO₂—R₈; (xix)—SO₂—NR₈R₉; or (xx) NR₈—CO—NHR₉; R₅ is (i) C₁-C₁₀ alkyl or C₂₋₁₀-alkenyleach optionally substituted by amino, N-lower alkylamino, N,N-diloweralkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR₁₀, —COR₁₄,—OCOR₁₄, —OR₁₀, C₅₋₁₀-heteroaryl, C₅₋₁₀-heteroaryloxy, orC₅₋₁₀-heteroaryl-C₁₋₁₀-alkoxy, halogen up to perhalo; (ii) C₃-C₁₀cycloalkyl, in which 1-3 carbon atoms are optionally independentlyreplaced by O, N or S; (iii) C₃₋₁₀-cycloalkenyl; (iv) partiallyunsaturated C₅₋₁₀-heterocyclyl; (v) aryl; (vi) heteroaryl; (vii)halogen; (viii) —CO—OR₁₀; (ix) —OCOR₁₀; (x) —OCO₂R₁₀; (xi) —CHO; (xii)cyano; (xiii) —OR₁₆; (xiv) —NR₁₀R₁₅; (xv) nitro; (xvi) —CO—NR₁₀R₁₁;(xvii) —NR₁₀—CO—R₁₂; (xviii) —NR₁₀—CO—OR₁₁; (xix) —NR₁₀—SO₂—R₁₂; (xx)—SR₁₆; (xxi) —SOR₁₆; (xxii) —SO₂—R₁₆; (xxiii) —SO₂—NR₁₀R₁₁; (xxiv)NR₁₀—CO—NHR₁₁; (xxv) amidino; (xxvi) guanidino; (xxvii) sulfo; (xxviii)—B(OH)₂; (xxix) —OCON(R₁₀)₂; or (xxx) —NR₁₀CON(R₁₀)₂; p=0, 1, 2, or 3R₈-R₁₁ are each independently H or C₁₋₆ alkyl R₁₂ is H, C₁₋₆-alkyl orC₅₋₁₀-aryl, R₁₃ is H, C₁₋₆-alkyl or C₁₋₆-alkoxy, R₁₄ is lower alkyl orphenyl; R₁₅ is lower alkyl, halogen, amino, N-lower alkyl amino,N,N-dilower alkylamino, N-lower alkanoylamino, OH, CN, COOR₁₀, —COR₁₄ or—OCOR₁₄; R₁₆ is hydrogen, C₁₋₆-alkyl optionally substituted by halogen,up to perhalo, or C₅₋₁₀-heteroaryl, and wherein Formulas 2 and 3encompass tautomers, optical isomers, or salts thereof.
 5. A process forthe preparation of a compound of Formula (I)

comprising replacing the hydroxy group of a compound of Formula 3

with a leaving group LG to form a compound of Formula 4

optionally isolating said compound of Formula 4; reacting a mixture ofsaid compound of Formula 4 and a compound of Formula 5

and optionally isolating said compound of Formula (I); wherein inFormulae 3, 4, 5 and (I) a and c are each independently —CR₅═, —N═, or—NR₆—, wherein one of a or c is —NR₆—; b is —CR₅═ or —N═; A is a 3-20atom, cyclic or polycyclic moiety, e.g., containing 1-4 rings, whichoptionally contain 1-3 N, O or S atoms per ring, and may optionally bearyl or heteroaryl, which cyclic or polycyclic moiety may optionally besubstituted up to 3 times by (i) C₁-C₁₀ alkyl or C₂-C₁₀-alkenyl, eachoptionally substituted with halogen up to perhalo; (ii) C₃-C₁₀cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR₈;(vii) —CO—R₈; (viii) cyano; (ix) —OR₈, (x) —NR₈R₁₃; (xi) nitro; (xii)—CO—NR₈R₉; (xiii) —C₁₋₁₀-alkyl-NR₈R₉; (xiv) —NR₈—CO—R₁₂; (xv)—NR₈—CO—OR₉; (xvi) —NR₈—SO₂—R₉; (xvii) —SR₈; (xviii) —SO₂—R₈; (xix)—SO₂—NR₈R₉; or (xx) NR₈—CO—NHR₉; R₁, R₆ and R₈-R₁₁ are eachindependently H or C₁₋₆ alkyl; R₂-R₅ are each independently (i) C₁₋₁₀alkyl or C₂₋₁₀-alkenyl each optionally substituted by amino, N-loweralkylamino, N,N-dilower alkylamino, N-lower alkanoylamino, hydroxy,cyano, —COOR₁₀, —COR₁₄, —OCOR₁₄, —OR₁₀, C₅₋₁₀-heteroaryl,C₅₋₁₀-heteroaryloxy, or C₅₋₁₀-heteroaryl-C₁₋₁₀-alkoxy, halogen up toperhalo; (ii) C₃-C₁₀ cycloalkyl, in which 1-3 carbon atoms areoptionally independently replaced by O, N or S; (iii)C₃₋₄₀-cycloalkenyl; (iv) partially unsaturated C₅₋₁₀-heterocyclyl; (v)aryl; (vi) heteroaryl; (vii) halogen; (viii) —CO—OR₁₀; (ix) —OCOR₁₀; (x)—OCO₂R₁₀; (xi) —CHO; (xii) cyano; (xiii) —OR₁₆; (xiv) —NR₁₀R₁₅; (xv)nitro; (xvi) —CO—NR₁₀R₁₁; (xvii) —NR₁₀—CO—R₁₂; (xviii) —NR₁₀—CO—OR₁₁;(xix) —NR₁₀—SO₂—R₁₂; (xx) —SR₁₆; (xxi) —SOR₁₆; (xxii) —SO₂—R₁₆; (xxiii)—SO₂—NR₁₀R₁₁; (xxiv) NR₁₀—CO—NHR₁₁; (xxv) amidino; (xxvi) guanidino;(xxvii) sulfo; (xxviii) —B(OH)₂; (xxix) —OCON(R₁₀)₂; or (xxx)—NR₁₀CON(R₁₀)₂; R₁₂ is H, C₁₋₆-alkyl or C₅₋₁₀-aryl, R₁₃ is H, C₁₋₆-alkylor C₁₋₆-alkoxy, R₁₄ is lower alkyl or phenyl; R₁₅ is lower alkyl,halogen, amino, N-lower alkyl amino, N,N-dilower alkylamino, N-loweralkanoylamino, OH, CN, COOR₁₀, —COR₁₄ or —OCOR₁₄; R₁₆ is hydrogen,C₁₋₆-alkyl optionally substituted by halogen, up to perhalo, orC₅₋₁₀-heteroaryl; p=0, 1, 2 or 3; and LG is Br or S-alkyl with theproviso that compound I is not


6. A process for the preparation of a compound of Formula I′

wherein Y is ═N— or ═CR₁₇, X is —(CH₂)_(x)—, —O—(CH₂)_(n)—,—S—(CH₂)_(n)—, —NR₇—CO—(CH₂)_(n)—, —NR₇—SO₂—(CH₂)_(n)—, —NR₇—(CH₂)_(n)—,or —(O)C—NR₇—, each n is an integer which is independently 0, 1, 2 or 3,x is 0-3 p is 0-3 a and c are each independently —CR5═, —N═, or —NR₆—,wherein one of a or c is —NR₆—, and b is —CR5═ or —N═; A is H, halogen,—CO—OR₈, —CO—R₈, cyano, —OR₈, —NR₈R₉, —CO—NR₈R₉, —NR₈—CO—R₉,—NR₈—CO—OR₉, —NR₈—SO₂—R₉, —SR₈, —SO₂—R₈, —SO₂—NR₈R₉, NR₈—CO—NHR₉, or Ais a 3-20 atom, cyclic or polycyclic moiety, containing 1-4 rings, whichoptionally contain 1-3 N, O or S atoms per ring, and may optionally bearyl or heteroaryl, which cyclic or polycyclic moiety may optionally besubstituted up to 3 times by (i) C₁-C₁₀ alkyl or C₂-C₁₀- alkenyl, eachoptionally substituted with halogen up to perhalo; (ii) C₃-C₁₀cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR₈;(vii) —CO—R₈; (viii) cyano; (ix) —OR₈; (x)(x) —NR₈R₁₃; (xi) nitro; (xii)—CO—NR₈R₉; (xiii) —C₁₋₁₀-alkyl-NR₈R₉; (xiv) —NR₈—CO—R₁₂; (xv)—NR₈CO—OR₉; (xvi) —NR₈—SO₂—R₉; (xvii) —SR₈; (xviii) —SO₂—R₈; (xix)SO₂—NR₈R₉; or (xx) NR₈—CO—NHR₉; Ring B is optionally independentlysubstituted up to 3 times in any position by R₅, R₁ and R₆₋₁₁ are eachindependently hydrogen or C₁₋₆alkyl, R₂-R₅ are each independently (i)hydrogen, (ii) C₁₋₁₀ alkyl or C₂₋₁₀-alkenyl each optionally substitutedby amino, N-lower alkylamino, N,N-dilower alkylamino, N-loweralkanoylamino, hydroxy, cyano, —COOR₁₀, —COR₁₄, —OCOR₁₄, —OR₁₀,C₅₋₁₀-heteroaryl, C₅₋₁₀-heteroaryloxy, or C₅₋₁₀-heteroaryl-C₁₋₁₀-alkoxy,halogen up to perhalo; (iii) C₃₋₁₀ cycloalkyl, in which 1-3 carbon atomsare optionally independently replaced by O, N or S; (iv)C₃₋₁₀-cycloalkenyl; (v) partially unsaturated C₅₋₁₀-heterocyclyl; (vi)aryl; (vii) heteroaryl; (viii) halogen; (ix) —CO—OR₁₀; (x) —OCOR₁₀; (xi)—OCO₂R₁₀; (xii) —CHO; (xiii) cyano; (xiv) —OR₁₆; (xv) —NR₁₀R₁₅; (xvi)nitro; (xvii) —CO—NR₁₀R₁₁; (xviii) —NR₁₀—CO—R₁₂; (xix) —NR₁₀—CO—OR₁₁;(xx) —NR₁₀—SO₂R₁₂; (xxi) —SR₁₆; (xxii) —SOR₁₆; (xxiii) —SO₂—R₁₆; (xxiv)—SO₂—NR₁₀R₁₁; (xxv) NR₁₀—CO—NHR₁₁; (xxvi) amidino; (xxvii) guanidine;(xxviii) sulfo; (xxix) —B(OH)₂; (xxx) —OCON(R₁₀)₂; or (xxxi)—NR₁₀CON(R₁₀)₂; R₁₂ is H, C₁₋₆-alkyl or C₅₋₁₀-aryl, R₁₃ is H, C₁₋₆-alkylor C₁₋₆-alkoxy, R₁₄ is C₁₋₆ alkyl or phenyl; R₁₅ is C₁₋₆ alkyl, halogen,amino, N-lower alkyl amino, N,N dilower alkylamino, N-loweralkanoylamino, OH, CN, COOR₁₀, —COR₁₄ or —OCOR₁₄; R₁₆ is hydrogen,C₁₋₆-alkyl optionally substituted by halogen, up to perhalo, orC₅₋₁₀-heteroaryl; and R₁₇ is H, C₁₋₆ alkyl or CN, or a pharmaceuticallyacceptable salt thereof, with the provisos that A is not hydrogen when xis 0, and that Formula I is not

said process comprising (a) reacting a compound of Formula II

with a compound of Formula III

in the presence of a base, to produce a compound of Formula IV

and optionally further reacting IV with arylboronic acid or A-NH₂, or(b) reacting a substituted benzoyl chloride with dimethylamine toproduce a compound of Formula V

wherein R′″ is (i) C₁-C₁₀ alkyl or C₂-C₁₀-alkenyl, each optionallysubstituted with halogen up to perhalo; (ii) C₃-C₁₀ cycloalkyl; (iii)aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR₈; (vii) —CO—R₈; (viii)cyano; (ix) —OR₈, (x) (x) —NR₈R₁₃; (xi) nitro; (xii) —CO—NR₈R₉; (xiii)—C₁₋₁₀-alkyl-NR₈R₉; (xiv) —NR₈—CO—R₁₂; (xv) —NR₈—CO—OR₉; (xvi)—NR₈—SO₂—R₉; (xvii) —SR₈; (xviii) —SO₂—R₈; (xix) —SO₂—NR₈R₉; or (xx)NR₈—CO—NHR₉, reacting V with chloro-2-amino-benzonitrile to produce acompound of Formula VI

and reacting VI with aminoindazole.
 7. A process for preparing

comprising reacting 3-fluoro-4-phenylbenzoic acid

with 4-bromo-2-fluorobiphenyl to produce2[(3-fluoro-4-phenylphenyl)carbonylamino]-benzamide

cyclizing to produce 2-(3-fluoro-1,1′-biphenyl-4-yl)-4(3H)-quinazolinone

reacting to produce 4-chloro-2-(3-fluoro-4-phenylphenyl)quinazoline

and then reacting with aminoindazole to produce


8. A process for the preparation of a compound of Formula (I)

comprising reacting a compound of Formula 3

with a compound of Formula

to produce a compound of Formula 2

cyclizing 2 to form a compound of Formula 3

replacing the hydroxy group of 3 with a leaving group LG to form acompound of Formula 4′

optionally isolating said compound of Formula 4′; reacting a mixture ofsaid compound of Formula 4′ and a compound of Formula 5

and optionally isolating said compound of Formula (I); wherein inFormulas 3, 4′, 5 and (I) a and c are each independently —CR₅═, —N═, or—NR₆—, wherein one of a or c is —NR₆—; b is —CR₅═ or —N═; A is a 3-20atom, cyclic or polycyclic moiety, e.g., containing 1-4 rings, whichoptionally contain 1-3 N, O or S atoms per ring, and may optionally bearyl or heteroaryl, which cyclic or polycyclic moiety may optionally besubstituted up to 3 times by (i) C₁-C₁₀ alkyl or C₂-C₁₀-alkenyl, eachoptionally substituted with halogen up to perhalo; (ii) C₃-C₁₀cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR₈;(vii) —CO—R₈; (viii) cyano; (ix) —OR₈, (x) —NR₈R₁₃; (xi) nitro; (xii)—CO—NR₈R₉; (xiii) —C₁₋₁₀-alkyl-NR₈R₉; (xiv) —NR₈—CO—R₁₂; (xv)—NR₈—CO—OR₉; (xvi) —NR₈—SO₂—R₉; (xvii) —SR₈; (xviii) —SO₂—R₈; (xix)—SO₂—NR₈R₉; or (xx) NR₈—CO—NHR₉; R₁, and R₆ and R₈-R₁₁ are eachindependently H or C₁₋₆ alkyl; R₂-R₅ are each independently (i) C₁₋₁₀alkyl or C₂₋₁₀-alkenyl each optionally substituted by amino, N-loweralkylamino, N,N-dilower alkylamino, N-lower alkanoylamino, hydroxy,cyano, —COOR₁₀, —COR₁₄, —OCOR₁₄, —OR₁₀, C₅₋₁₀-heteroaryl,C₅₋₁₀-heteroaryloxy, or C₅₋₁₀-heteroaryl-C₁₋₁₀-alkoxy, halogen up toperhalo; (ii) C₃-C₁₀ cycloalkyl, in which 1-3 carbon atoms areoptionally independently replaced by O, N or S; (iii)C₃₋₄₀-cycloalkenyl; (iv) partially unsaturated C₅₋₁₀-heterocyclyl; (v)aryl; (vi) heteroaryl; (vii) halogen; (viii) —CO—OR₁₀; (ix) —OCOR₁₀; (x)—OCO₂R₁₀; (xi) —CHO; (xii) cyano; (xiii) —OR₁₆; (xiv) —NR₁₀R₁₅; (xv)nitro; (xvi) —CO—NR₁₀R₁₁; (xvii) —NR₁₀—CO—R₁₂; (xviii) —NR₁₀—CO—OR₁₁;(xix) —NR₁₀—SO₂—R₁₂; (xx) —SR₁₆; (xxi) —SOR₁₆; (xxii) —SO₂—R₁₆; (xxiii)—SO₂—NR₁₀R₁₁; (xxiv) NR₁₀—CO—NHR₁₁; (xxv) amidino; (xxvi) guanidino;(xxvii) sulfo; (xxviii) —B(OH)₂; (xxix) —OCON(R₁₀)₂; or (xxx)—NR₁₀—CON(R₁₀)₂; R₁₂ is H, C₁₋₆-alkyl or C₅₋₁₀-aryl, R₁₃ is H,C₁₋₆-alkyl or C₁₋₆-alkoxy, R₁₄ is lower alkyl or phenyl; R₁₅ is loweralkyl, halogen, amino, N-lower alkyl amino, N,N-dilower alkylamino,N-lower alkanoylamino, OH, CN, COOR₁₀, —COR₁₄ or —OCOR₁₄; R₁₆ ishydrogen, C₁₋₆-alkyl optionally substituted by halogen, up to perhalo,or C₅₋₁₀-heteroaryl; and p=0, 1, 2 or 3; LG is Cl; and Q is CN; with theproviso that compound I is not


9. A process for the preparation of a compound of Formula (I)

comprising reacting a compound of Formula 4′

and a compound of Formula 5

wherein in Formulas 3, 4′, 5 and (I) a and c are each independently—CR₅═, —N═, or —NR₆—, wherein one of a or c is —NR₆—; b is —CR₅═ or —N═;A is a 3-20 atom, cyclic or polycyclic moiety, e.g., containing 1-4rings, which optionally contain 1-3 N, O or S atoms per ring, and mayoptionally be aryl or heteroaryl, which cyclic or polycyclic moiety mayoptionally be substituted up to 3 times by (i) C₁-C₁₀ alkyl orC₂-C₁₀-alkenyl, each optionally substituted with halogen up to perhalo;(ii) C₃-C₁₀ cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi)—CO—OR₈; (vii) —CO—R₈; (viii) cyano; (ix) —OR₈, (x) —NR₈R₁₃; (xi) nitro;(xii) —CO—NR₈R₉; (xiii) —C₁₋₁₀-alkyl-NR₈R₉; (xiv) —NR₈—CO—R₁₂; (xv)—NR₈—CO—OR₉; (xvi) —NR₈—SO₂—R₉; (xvii) —SR₈; (xviii) —SO₂—R₈; (xix)—SO₂—NR₈R₉; or (xx) NR₈—CO—NHR₉; R₁, R₆ and R₈-R₁₁ are eachindependently H or C₁₋₆ alkyl; R₂-R₅ are each independently (i) C₁₋₁₀alkyl or C₂₋₁₀-alkenyl each optionally substituted by amino, N-loweralkylamino, N,N-dilower alkylamino, N-lower alkanoylamino, hydroxy,cyano, —COOR₁₀, —COR₁₄, —OCOR₁₄, —OR₁₀, C₅₋₁₀-heteroaryl,C₅₋₁₀-heteroaryloxy, or C₅₋₁₀-heteroaryl-C₁₋₁₀-alkoxy, halogen up toperhalo; (ii) C₃-C₁₀ cycloalkyl, in which 1-3 carbon atoms areoptionally independently replaced by O, N or S; (iii)C₃₋₄₀-cycloalkenyl; (iv) partially unsaturated C₅₋₁₀-heterocyclyl; (v)aryl; (vi) heteroaryl; (vii) halogen; (viii) —CO—OR₁₀; (ix) —OCOR₁₀; (x)—OCO₂R₁₀; (xi) —CHO; (xii) cyano; (xiii) —OR₁₆; (xiv) —NR₁₀R₁₅; (xv)nitro; (xvi) —CO—NR₁₀R₁₁; (xvii) —NR₁₀—CO—R₁₂; (xviii) —NR₁₀—CO—OR₁₁;(xix) —NR₁₀—SO₂—R₁₂; (xx) —SR₁₆; (xxi) —SOR₁₆; (xxii) —SO₂—R₁₆; (xxiii)—SO₂—NR₁₀R₁₁; (xxiv) NR₁₀—CO—NHR₁₁; (xxv) amidino; (xxvi) guanidino;(xxvii) sulfo; (xxviii) —B(OH)₂; (xxix) —OCON(R₁₀)₂; or (xxx)—NR₁₀—CON(R₁₀)₂; R₁₂ is H, C₁₋₆-alkyl or C₅₋₁₀-aryl, R₁₃ is H,C₁₋₆-alkyl or C₁₋₆-alkoxy, R₁₄ is lower alkyl or phenyl; R₁₅ is loweralkyl, halogen, amino, N-lower alkyl amino, N,N-dilower alkylamino,N-lower alkanoylamino, OH, CN, COOR₁₀, —COR₁₄ or —OCOR₁₄; R₁₆ ishydrogen, C₁₋₆-alkyl optionally substituted by halogen, up to perhalo,or C₅₋₁₀-heteroaryl; and p=0, 1, 2 or 3; with the proviso that compoundI is not


10. A process for the preparation of a compound of Formula 3

from a compound of Formula 2

comprising mixing said compound of Formula 2, where Q is —CN,—with about0.1 N to about 10 N (or 20%) aqueous hydroxide and about 3 to about 30%H₂O₂, or with about 0.5 to 2.5 M mineral acid, heating the mixture froma temperature of about 30° C. to about 120° C.; wherein A is a 3-20atom, cyclic or polycyclic moiety, e.g., containing 1-4 rings, whichoptionally contain 1-3 N, O or S atoms per ring, and may optionally bearyl or heteroaryl, which cyclic or polycyclic moiety may optionally besubstituted up to 3 times by (i) C₁-C₁₀ alkyl or C₂-C₁₀-alkenyl, eachoptionally substituted with halogen up to perhalo; (ii) C₃-C₁₀cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR₈;(vii) —CO—R₈; (viii) cyano; (ix) —OR₈, (x) —NR₈R₁₃; (xi) nitro; (xii)—CO—NR₈R₉; (xiii) —C₁₋₁₀-alkyl-NR₈R₉; (xiv) —NR₈—CO—R₁₂; (xv)—NR₈—CO—OR₉; (xvi) —NR₈—SO₂—R₉; (xvii) —SR₈; (xviii) —SO₂—R₈; (xix)—SO₂—NR₈R₉; or (xx) NR₈—CO—NHR₉; R₅ is (i) C₁₋₁₀ alkyl or C₂₋₁₀-alkenyleach optionally substituted by amino, N-lower alkylamino, N,N-diloweralkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR₁₀, —COR₁₄,—OCOR₁₄, —OR₁₀, C₅₋₁₀-heteroaryl, C₅₋₁₀-heteroaryloxy, orC₅₋₁₀-heteroaryl-C₁₋₁₀-alkoxy, halogen up to perhalo; (ii) C₃-C₁₀cycloalkyl, in which 1-3 carbon atoms are optionally independentlyreplaced by O, N or S; (iii) C₃₋₁₀-cycloalkenyl; (iv) partiallyunsaturated C₅₋₁₀-heterocyclyl; (v) aryl; (vi) heteroaryl; (vii)halogen; (viii) —CO—OR₁₀; (ix) —OCOR₁₀; (x) —OCO₂R₁₀; (xi) —CHO; (xii)cyano; (xiii) —OR₁₆; (xiv) —NR₁₀R₁₅; (xv) nitro; (xvi) —CO—NR₁₀R₁₁;(xvii) —NR₁₀—CO—R₁₂; (xviii) —NR₁₀—CO—OR₁₁; (xix) —NR₁₀—SO₂—R₁₂; (xx)—SR₁₆; (xxi) —SOR₁₆; (xxii) —SO₂—R₁₆; (xxiii) —SO₂—NR₁₀R₁₁; (xxiv)NR₁₀—CO—NHR₁₁; (xxv) amidino; (xxvi) guanidino; (xxvii) sulfo; (xxviii)—B(OH)₂; (xxix) —OCON(R₁₀)₂; or (xxx) —NR₁₀CON(R₁₀)₂; p=0, 1, 2, or 3R₈-R₁₁ are each independently H or C₁₋₆ alkyl R₁₂ is H, C₁₋₆-alkyl orC₅₋₁₀-aryl, R₁₃ is H, C₁₋₆-alkyl or C₁₋₆-alkoxy, R₁₄ is lower alkyl orphenyl; R₁₅ is lower alkyl, halogen, amino, N-lower alkyl amino,N,N-dilower alkylamino, N-lower alkanoylamino, OH, CN, COOR₁₀, —COR₁₄ or—OCOR₁₄; R₁₆ is hydrogen, C₁₋₆-alkyl optionally substituted by halogen,up to perhalo, or C₅₋₁₀-heteroaryl, and wherein Formulas 2 and 3encompass tautomers, optical isomers, or salts thereof.
 11. A processfor the preparation of a compound of Formula 3,

from a carboxylic acid of Formula A-CO₂H and a compound of Formula 1,

comprising in a single vessel, treating said carboxylic acid with achlorinating agent, with optional addition of a catalytic amount of DMF,to form an acid chloride of Formula A-CO—Cl; adding a non-nucleophilicamine base and a non-protic solvent with stirring at room temperature toform a compound of Formula 2;

and adding of a base and heating the mixture at about 30 to 120° C.; fora sufficient time to effect reaction; wherein Q is CN, A is a 3-20 atom,cyclic or polycyclic moiety, e.g., containing 1-4 rings, whichoptionally contain 1-3 N, O or S atoms per ring, and may optionally bearyl or heteroaryl, which cyclic or polycyclic moiety may optionally besubstituted up to 3 times by (i) C₁-C₁₀ alkyl or C₂-C₁₀-alkenyl, eachoptionally substituted with halogen up to perhalo; (ii) C₃-C₁₀cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR₈;(vii) —CO—R₈; (viii) cyano; (ix) —OR₈, (x) —NR₈R₁₃; (xi) nitro; (xii)—CO—NR₈R₉; (xiii) —C₁₋₁₀-alkyl-NR₈R₉; (xiv) —NR₈—CO—R₁₂; (xv)—NR₈—CO—OR₉; (xvi) —NR₈—SO₂—R₉; (xvii) —SR₈; (xviii) —SO₂—R₈; (xix)—SO₂—NR₈R₉; or (xx) NR₈—CO —NHR₉; R₅ is (i) C₁₋₁₀ alkyl or C₂₋₁₀-alkenyleach optionally substituted by amino, N-lower alkylamino, N,N-diloweralkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR₁₀, —COR₁₄,—OCOR₁₄, —OR₁₀, C₅₋₁₀-heteroaryl, C₅₋₁₀-heteroaryloxy, orC₅₋₁₀-heteroaryl-C₁₋₁₀-alkoxy, halogen up to perhalo; (ii) C₃-C₁₀cycloalkyl, in which 1-3 carbon atoms are optionally independentlyreplaced by O, N or S; (iii) C₃₋₁₀-cycloalkenyl; (iv) partiallyunsaturated C₅₋₁₀-heterocyclyl; (v) aryl; (vi) heteroaryl; (vii)halogen; (viii) —CO—OR₁₀; (ix) —OCOR₁₀; (x) —OCO₂R₁₀; (xi) —CHO; (xii)cyano; (xiii) —OR₁₆; (xiv) —NR₁₀R₁₅; (xv) nitro; (xvi) —CO—NR₁₀R₁₁;(xvii) —NR₁₀—CO—R₁₂; (xviii) —NR₁₀—CO—OR₁₁; (xix) —NR₁₀—SO₂—R₁₂; (xx)—SR₁₆; (xxi) —SOR₁₆; (xxii) —SO₂—R₁₆; (xxiii) —SO₂—NR₁₀R₁₁; (xxiv)NR₁₀—CO—NHR₁₁; (xxv) amidino; (xxvi) guanidino; (xxvii) sulfo; (xxviii)—B(OH)₂; (xxix) —OCON(R₁₀)₂; or (xxx) —NR₁₀—OCON(R₁₀)₂; p=0, 1, 2, or 3R₈-R₁₁ are each independently H or C₁₋₆ alkyl R₁₂ is H, C₁₋₆-alkyl orC₅₋₁₀-aryl, R₁₃ is H, C₁₋₆-alkyl or C₁₋₆-alkoxy, R₁₄ is lower alkyl orphenyl; R₁₅ is lower alkyl, halogen, amino, N-lower alkyl amino,N,N-dilower alkylamino, N-lower alkanoylamino, OH, CN, COOR₁₀, —COR₁₄ or—OCOR₁₄; R₁₆ is hydrogen, C₁₋₆-alkyl optionally substituted by halogen,up to perhalo, or C₅₋₁₀-heteroaryl, and wherein Formulas 2 and 3encompass tautomers, optical isomers, or salts thereof.
 12. A processfor the preparation of a compound of Formula (I)

comprising replacing the hydroxy group of a compound of Formula 3

with a leaving group Cl to form a compound of Formula 4′

optionally isolating said compound of Formula 4; reacting a mixture ofsaid compound of Formula 4 and a compound of Formula 5

and optionally isolating said compound of Formula (I); wherein inFormulae 3, 4′, 5 and (I) a and c are each independently —CR₅═, —N═, or—NR₆—, wherein one of a or c is —NR₆—; b is —CR₅═ or —N═; A is a 3-20atom, cyclic or polycyclic moiety, e.g., containing 1-4 rings, whichoptionally contain 1-3 N, O or S atoms per ring, and may optionally bearyl or heteroaryl, which cyclic or polycyclic moiety may optionally besubstituted up to 3 times by (i) C₁-C₁₀ alkyl or C₂-C₁₀-alkenyl, eachoptionally substituted with halogen up to perhalo; (ii) C₃-C₁₀cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR₈;(vii) —CO—R₈; (viii) cyano; (ix) —OR₈, (x) —NR₈R₁₃; (xi) nitro; (xii)—CO—NR₈R₉; (xiii) —C₁₋₁₀-alkyl-NR₈R₉; (xiv) —NR₈—CO—R₁₂; (xv)—NR₈—CO—OR₉; (xvi) —NR₈—SO₂—R₉; (xvii) —SR₈; (xviii) —SO₂—R₈; (xix)—SO₂—NR₈R₉; or (xx) NR₈—CO—NHR₉; R₁, R₆ and R₈-R₁₁ are eachindependently H or C₁₋₆ alkyl; R₂-R₅ are each independently (i) C₁₋₁₀alkyl or C₂₋₁₀-alkenyl each optionally substituted by amino, N-loweralkylamino, N,N-dilower alkylamino, N-lower alkanoylamino, hydroxy,cyano, —COOR₁₀, —COR₁₄, —OCOR₁₄, —OR₁₀, C₅₋₁₀-heteroaryl,C₅₋₁₀-heteroaryloxy, or C₅₋₁₀-heteroaryl-C₁₋₁₀-alkoxy, halogen up toperhalo; (ii) C₃-C₁₀ cycloalkyl, in which 1-3 carbon atoms areoptionally independently replaced by O, N or S; (iii)C₃₋₄₀-cycloalkenyl; (iv) partially unsaturated C₅₋₁₀-heterocyclyl; (v)aryl; (vi) heteroaryl; (vii) halogen; (viii) —CO—OR₁₀; (ix) —OCOR₁₀; (x)—OCO₂R₁₀; (xi) —CHO; (xii) cyano; (xiii) —OR₁₆; (xiv) —NR₁₀R₁₅; (xv)nitro; (xvi) —CO—NR₁₀R₁₁; (xvii) —NR₁₀—CO—R₁₂; (xviii) —NR₁₀—CO—OR₁₁;(xix) —NR₁₀—SO₂—R₁₂; (xx) —SR₁₆; (xxi) —SOR₁₆; (xxii) —SO₂—R₁₆; (xxiii)—SO₂—NR₁₀R₁₁; (xxiv) NR₁₀—CO—NHR₁₁; (xxv) amidino; (xxvi) guanidino;(xxvii) sulfo; (xxviii) —B(OH)₂; (xxix) —OCON(R₁₀)₂; or (xxx)—NR₁₀CON(R₁₀)₂; R₁₂ is H, C₁₋₆-alkyl or C₅₋₁₀-aryl, R₁₃ is H, C₁₋₆-alkylor C₁₋₆-alkoxy, R₁₄ is lower alkyl or phenyl; R₁₅ is lower alkyl,halogen, amino, N-lower alkyl amino, N,N-dilower alkylamino, N-loweralkanoylamino, OH, CN, COOR₁₀, —COR₁₄ or —OCOR₁₄; R₁₆ is hydrogen,C₁₋₆-alkyl optionally substituted by halogen, up to perhalo, orC₅₋₁₀-heteroaryl; p=0, 1, 2 or 3; and LG is Br or S-alkyl with theproviso that compound I is not